The invention provides pyrrolo carboxamide compounds as modulators for the orphan nuclear receptor RORγ and methods for treating RORγ mediated chronic inflammatory and autoimmune diseases by administrating these novel RORγ modulators to a human or a mammal in need thereof.

The retinoid-receptor related orphan receptors consist of three family members, namely RORα (Beckerandre et al., Biochem. Biophys. Res. Commun. 1993, 194:1371), RORβ (Andre et al., Gene 1998, 516:277) and RORγ (He et al., Immunity 1998, 9:797) and constitute the NR1F (ROR/RZR) subgroup of the nuclear receptor superfamily (Mangelsdorf et al., Cell 1995, 83:835).

The nuclear receptor superfamily shares common modular structural domains consisting of a hypervariable N-terminal domain, a conserved DNA binding domain (DBD), a hinge region and a conserved ligand-binding domain (LBD). The DBD targets the receptor to specific DNA sequences (nuclear hormone response elements or NREs) and the LBD functions in the recognition of endogenous or exogenous chemical ligands. A constitutive transcriptional activation domain is found at the N-terminus (AF1) and a ligand regulated transcriptional activation domain is embedded within the C-terminal LBD of typical NRs. The nuclear receptors can exist in a transcriptional activating or repressing state when bound to their target NREs. The basic mechanism of gene activation involves ligand dependent exchange of co-regulatory proteins, namely co-activators and co-repressors (McKenna et al., Endocrine Rev. 1999, 20:321). A NR in the repressing state is bound to its DNA recognition element and is associated with co-repressor proteins that recruit histone-deacetylases (HDACs). In the presence of an agonist, co-repressors are exchanged for coactivators that recruit transcription factors, which contribute to assembling of a chromatin-remodelling complex, which relieves transcriptional repression and stimulates transcriptional initiation via histone acetylation. The AF-2 domain of the LBD acts as a ligand dependant molecular switch presenting interaction surfaces for co-repressor or co-activator proteins and providing with a conserved mechanism for gene activation or repression that is shared by the members of the nuclear receptor superfamily.

The members of the NR1F family of nuclear receptors (such as RORγ) have been considered to be constitutively active transcription factors in the absence of known ligands, which is similar to the estrogen-related receptor alpha (Vanacker et al., Mol. Endocrinol. 1999, 13:764). Most recently, 7-oxygenated oxysterols were identified to be high affinity ligands for RORα and RORγ (Wang et al., J. Biol. Chem. 2010, 285:5013). 7-Hydroxycholesterol is a key metabolite during the conversion of cholesterol into bile acids, but to date it is not clear whether it is a true endogenous ligand for the RORs. In any case it can be expected that inverse agonists of RORγ should reduce the transcriptional activity of RORγ and influence the biological pathways controlled by RORγ.

The RORs are expressed as isoforms arising from differential splicing or alternative transcriptional start sites. So far, isoforms have been described that differ only in their N-terminal domain (A/B-domain). In humans, four different RORα isoforms have been identified (RORα 1-4) while only two isoforms are known for both RORβ (1 and 2) and RORγ (1 and 2) (Andre et al., Gene 1998, 216:277; Villey et al., Eur. J. Immunol. 1999, 29:4072). RORγ is used herein as a term describing both, RORγ1 and/or RORγ2 (also called RORγt).

The ROR isoforms show different tissue expression patterns and regulate different target genes and physiological pathways. For example, the RORγt is highly restricted to CD4⁺CD8⁺ thymocytes and to interleukin-17 (IL-17) producing T cells while other tissues express RORγ1 (Eberl et al., Science 2004, 305:248, Zhou and Littmann, Curr. Opin. Immunol. 2009, 21:146).

RORs exhibit a structural architecture that is typical of nuclear receptors. RORs contain four major functional domains: an amino-terminal (A/B) domain, a DNA-binding domain, a hinge domain and a ligand-binding domain (Evans et al., Science 1988, 240:889). The DBD consists of two highly conserved zinc finger motifs involved in the recognition of ROR response elements (ROREs) which consist of the consensus motif AGGTCA preceded by an AT-rich sequence (Andre et al., Gene 1998, 216:277) which is similar to that of the nuclear receptors Rev-ErbAα and Rev-Erbβ (NR1D1 and D2, respectively) (Giguere et al., Genomics 1995, 28:596). These recognition elements do also show high similarity to those identified for the estrogen related receptors and in particular ERRα (ERRs, NR3B1, -2, -3) (Vanacker et al., Mol. Endocrinol. 1999, 13:764), steroidogenic factor 1 (SF-1, NR5A) and NGFI-B (NR4A1, -2, -3) (Wilson et al., Mol. Cell. Biol. 1993, 13:5794).

RORα is highly expressed in different brain regions and most highly in cerebellum and thalamus. RORα knock-out mice show ataxia with strong cerebellar atrophy, highly similar to the symptoms displayed in the so-called staggerer mutant mouse (RORα^sg/sg). This mouse carries mutations in RORα that results in a truncated RORα which does not contain a LBD (Hamilton et al., Nature 1996, 379:736).

Analysis of RORα^sg/sg staggerer-mice have revealed a strong impact on lipid metabolism beyond the CNS defects, namely significant decreases in serum and liver triglyceride, reduced serum HDL cholesterol levels and reduced adiposity. SREBP1c and the cholesterol transporters ABCA1 and ABCG1 are reduced in livers of staggerer mice and CHIP analysis suggest that RORα is directly recruited to and regulates the SREBP1c promoter. In addition, PGC1α, PGC1β, lipin1 and β2-adrenergic receptor were found to be increased in tissues such as liver or white and brown adipose tissue, which may help to explain the observed resistance to diet-induced obesity in staggerer mice (Lau et al., J. Biol. Chem. 2008, 283:18411).

RORβ expression is mainly restricted to the brain and most abundantly found in the retina. RORβ knock-out mice display a duck-like gait and retinal degeneration which leads to blindness (Andre et al., EMBO J. 1998, 17:3867). The molecular mechanisms behind this retinal degeneration are still poorly understood.

RORγ (particularly RORγt) null-mutant mice lack lymph nodes and Peyer's patches (Eberl and Littmann, Immunol. Rev. 2003, 195:81) and lymphatic tissue inducer (LTi) cells are completely absent from spleen mesentery and intestine. In addition, the size of the thymus and the number of thymocytes is greatly reduced in RORy null mice (Sun et al., Science 2000, 288:2369) due to a reduction in double-positive CD4⁺CD8⁺ and single positive CD4^-CD8⁺ or CD4⁺CD8^- cells suggesting a very important role of RORγt in thymocyte development.

Thymocyte development follows a complex program involving coordinated cycles of proliferation, differentiation, cell death and gene recombination in cell populations dedicated by their microenvironment. Pluripotent lymphocyte progenitors migrating from fetal liver or adult bone marrow to the thymus are being committed to the T-cell lineage. They develop through a series of steps from CD4^-CD8^- double negative cells to CD4⁺CD8⁺ cells and those with low affinity towards self-MHC peptides are eliminated by negative selection. These develop further into CD4^-CD8⁺ (killer) or CD4⁺CD8^- (helper) T-cell lineages. RORγt is not expressed in double negative and little expressed in immature single negative thymocytes (He et al., J. Immunol. 2000, 164:5668), while highly upregulated in double-positive thymocytes and downregulated during differentiation in single-positive thymocytes. RORγ deficiency results in increased apoptosis in CD4⁺CD8⁺ cells and the number of peripheral blood thymocytes is decreased by 6-fold (10-fold CD4⁺ and 3-fold CD8⁺ thymocytes).

Recent experiments in a model of ovalbumin (OVA)-induced inflammation in mice, as a model for allergic airway disease, demonstrated a severe impairment of the development of the allergic phenotype in the RORγ KO mice with decreased numbers of CD4⁺ cells and lower Th2 cytokine/chemokine protein and mRNA expression in the lungs after challenge with OVA (Tilley et al., J. Immunol. 2007, 178:3208). IFN-γ and IL-10 production were increased in splenocytes following re-stimulation with the OVA antigen compared to wt splenocytes suggesting a shift towards a Th1 type immune response on cost of a reduction of Th2 type response. This suggests that down-modulation of RORγ transcriptional activity with a ligand could result in a similar shift of the immune response towards a Th1 type response, which could be beneficial in the treatment of certain pulmonary diseases like asthma, chronic obstructive pulmonary disease (COPD) or allergic inflammatory conditions.

T-helper cells were previously considered to consist of Th1 and Th2 cells. However, a new class of Th cells, the Th17 cells, which produce IL-17, were also identified as a unique class of T-cells that are considered to be pro-inflammatory. They are recognized as key players in autoimmune and inflammatory diseases since IL-17 expression has been associated with many inflammatory diseases such as rheumatoid arthritis, systemic lupus erythematosus (SLE) and allograft rejection. (Tesmer et al., Immunol. Rev. 2008, 223:87).

RORyt is exclusively expressed in cells of the immune system and has been identified as a master regulator of Th17 cell differentiation. Expression of RORγt is induced by TGF-beta or IL-6 and overexpression of RORγt results in increased Th17 cell lineage and IL-17 expression. RORγt KO mice show very little Th17 cells in the intestinal lamina propria and demonstrate an attenuated response to challenges that usually lead to autoimmune disease (Ivanov et al., Cell 2006, 126:1121).

Inhibition of IL-17 production via inhibition of Th17 cell development may also be advantageous in atopic dermatitis and psoriasis where IL-17 is deeply involved. Interestingly, recent evidence was presented that IL-10 suppresses the expression of IL-17 secreted by both, macrophages and T-cells. In addition, the expression of the Th17 transcription factor RORγt was suppressed (Gu et al., Eur. J. Immunol. 2008, 38:1807). Moreover, IL-10 deficient mice provide a good model for inflammatory bowel disease (IBD) where a shift towards a Th1 type inflammatory response is frequently observed. Oral IL-10 delivery poses a potential treatment option for IBD.

The proinflammatory actions of IL-17 producing Th17 cells are counteracted by another T-helper cell type, so-called regulatory T-cells or Tregs. Naive T-cells are differentiated into Tregs upon stimulation by TGFβ. This results in upregulation of the transcriptional modulator FoxP3 resulting in CD4⁺FoxP3⁺ Tregs. In case the naive T-cells are co-stimulated by IL-6, FoxP3 expression is suppressed and RORγt expression is induced. These CD4⁺FoxP3^-RORγt⁺ T-helper cells then differentiate into IL-17 producing Th17 cells. (reviewed in Awasthi and Kuchroo, Int. Immunol. 2009, 21:489 and Zhou and Littmann, Curr. Opin. Immunol. 2009, 21:146). Several lines of evidence suggest that these Th17 cells are responsible for the etiology of a whole range of autoimmune diseases such as multiple sclerosis, rheumatoid arthritis, ankylosing spondylitis, psoriasis, Crohn's disease and other types of inflammatory bowel disease, lupus erythematosus and asthma. The severity of disease seems to correlate with the presence of IL-17⁺ Th17 cells and it is believed that interception of RORγt by a small molecule inverse agonist or antagonist should result in a reduction of these IL-17⁺ Th17 cells ultimately leading to alleviation of disease symptoms and outcome (Crome et al., Clin. Exp. Immunol. 2010, 159:109).

It was reported that cholesterol and its sulfated derivatives might function as RORα ligands and in particular cholesterol-sulfate could restore transcriptional activity of RORα in cholesterol-depleted cells (Kallen et al., Structure 2002, 10:1697). Previously, melatonin (Missbach et al., J. Biol. Chem. 1998, 271:13515) and thiazolidinediones were suggested to bind to RORα (Wiesenberg et al., Nucleic Acid Res. 1995, 23:327). However, none of these have been shown to be functional ligands of RORα or of any other of the RORs. Certain retinoids including all-trans retinoid acid have been demonstrated to bind to RORβ and function as partial antagonists for RORβ but not RORα (Stehlin-Gaon et al., Nat. Struct. Biol. 2003, 10:820).

Recently, 7-oxygenated sterols such as 7-hydroxy-cholesterol and 7-keto-cholesterol were identified as highly potent modulators of RORγ activity (Wang et al., J. Biol. Chem. 2010, 285:5013) in in vitro assays. The same group of investigators also found that a known LXR agonist, T0901317 ([N-(2,2,2-trifluoroethyl)-N-[4-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl]phenyl]-benzenesulfonamide]) acts as a RORγ inverse agonist at submicromolar potency (Kumar et al., Mol. Pharmacol. 2010, 77:228). In neither case, however, in vivo data were obtained that demonstrate a beneficial impact of these RORγ modulating compounds. In case of the 7-oxysterols their endogenous presence as metabolites naturally produced by the body itself as well as their rapid turnover and their biological activities on many cellular proteins prevent a meaningful animal study that allows drawing conclusions on the role of RORy. In case of the T0901317 its polypharmacodynamic properties, acting on at least six different nuclear receptors (LXRα/β, FXR, PXR, RORα/γ) prevents its usefulness as a drug candidate for the development in an autoimmune disease application (Houck et al., Mol. Genet. Metab. 2004, 83:184; Xue et al., Bioorg. Med. Chem. 2007, 15:2156).

WO2004/060870 describes pyrrolo carboxamide compounds of structure (A) as modulators of the CB1 receptor useful for treating and preventing eating disorders, obesity, type II diabetes and the like,

• wherein R¹ is H or lower alkyl;
• R² is limited to C_1-8-alkyl, (CH₂)_{0 or 1}-cyclolalkyl or a (CH₂)_{0 or 1} connected to a 5- or 6-membered saturated heterocycle or 5- or 6-membered heteroaromatic ring, wherein the corresponding ring can be optionally substituted. Remarkably, C_1-8-alkyl can not be optionally substituted; R³ is limited to optionally substituted cycloalkyl or optionally substituted phenyl;
• R⁴ is limited to optionally substituted phenyl, naphthyl or a 5- or 6-membered heteroaromatic ring. Possible substitutents for R⁴ are OH, C_1-8-alkyl, O-C_1-8-alkyl, halogen, NO₂, C_1-8-halogenated alkyl, O-C_1-8-halogenated alkyl, CN, SO₂-C_1-8-alkyl and optionally alkylated amine. Remarkably, R⁴ can not be substituted e.g. with C_0-8-alkylene-CONR₂, C_0-8-alkylene-SO₂NR₂, C_0-8-alkylene-NRCOR or C_0-8-alkylene-NRSO₂R.

WO2005/108393 describes pyrrolo carboxamide compounds of structure (A) as modulators of the CB1 receptor, wherein R³ is limited to a 5- or 6-membered saturated heterocyclic ring containing 1 or 2 heteroatoms independently selected from N or O, which is optionally substituted by OH, C_1-8-alkyl, O-C_1-8-alkyl, C(=O)O-C_1-8-alkyl or being condensed with a phenyl ring and R⁴ is limited to phenyl, optionally substituted only by OH, C_1-8-alkyl, halo-C_1-8-alkyl, O-C_1-8-alkyl, O-halo-C_1-6-alkyl and halogen.

WO2004/060888 describes pyrrolo carboxamide compounds of structure (A) as modulators of the CB1 receptor, wherein R⁴ is limited to optionally substituted 4-thiazolyl.

In none of the above mentioned publications a 4-membered heterocycle is claimed as substituent for R¹ or R². Furthermore there are no references, that these pyrrolo carboxamide compounds have RORy receptor modulating activity.

US2009/0036421 (equivalent to WO2007/097276) describes pyrrolo carboxamide compounds of structure (B) as 5-HT_2B and 5-HT₇ receptor modulators for the treatment of irritable bowel syndrome

However, there is no reference, that compounds have RORγ receptor modulating activity.

In WO2006/012642 are pyrrolo-3-carboxamides described, in particular compounds wherein a C_1-3-alkylene-cycloalkyl group is connected to the pyrrolo nitrogen, e.g. structures (C) and (C').

WO2004/103968 describes 2-phenylsulfopyrroles wherein the sulfonyl residue is restricted to optionally substituted phenyl.

WO2011/042477 describes substituted pyrroles and imidazoles as estrogen receptor ligands. However no pyrrolo-3-carboxamides are disclosed, which have a C_1-3-alkylene-cycloalkyl group connected to the pyrrolo nitrogen.

The Chemical Abstract database lists several pyrrolo carboxamides with no accompanying literature references, which are excluded via provisos form the presented claims, e.g.

WO2012/144661 describes substituted pyrroles as TRPV4 inhibitors with a very broad coverage of various substituents. However no pyrrolo-3-carboxamides are disclosed, which fall in the scope of the present invention. In particular, no compounds with a cycloalkyl group connected via a linker (e.g. alkylene or SO₂) to the pyrrole nitrogen are specifically disclosed.

WO2011/071996 discloses N-benzyl pyrrole compounds useful as inhibitors of the enzyme Fatty Acid Amide Hydrolase (FAAH).

Modulators of the RORy receptor were recently disclosed in WO2011/107248, WO2011/112263, WO2011/112264, WO2011/115892, WO2012/027965, WO2012/028100, WO2012/064744, WO2012/100732, WO2012/100734, WO2012/106995, WO2012/139775, WO2012/147916 and WO2012/158784, which are based upon other structural classes.

It is therefore the object of the present invention to provide compounds, which bind to the orphan nuclear receptors RORγ1 and/or RORγt and, thus, to open new methods for treating diseases associated with the modulation of RORγ, such as autoimmune diseases, inflammatory skin diseases or multiple sclerosis.

This object is solved by claims 1 to 23.

Thus, the present invention provides pyrrolo carboxamides compounds as RORγ modulators, which can be used for treating or preventing a disease or disorder associated with the inactivation or activation of the RORγ receptor.

The present invention relates to a RORγ modulator which is based on a pyrrolo carboxamide scaffold for use in the treatment or prophylaxis of a disease or disorder associated with the inhibition or activation of RORγ.

When treating the disease or disorder associated with the modulation of the RORγ receptor, the activity of said receptor is preferably reduced.

Preferably, the disease or disorder is selected from the group consisting of autoimmune diseases. Autoimmune diseases comprise a group of diseases with a similar etiology of an overshooting immune response against endogenous targets resulting in chronic inflammation and physical disabilities or other severe symptoms. Autoimmune diseases comprise e.g. rheumatoid arthritis, ankylosing spondylitis, lupus erythematosus, psoriasis, atopic eczema, inflammatory bowel diseases such as Crohn's disease, respiratory diseases such as asthma or chronic obstructive pulmonary disease (COPD), infectious diseases such as mucosal leishmaniasis, multiple sclerosis, systemic sclerosis, type 1 diabetes, Kawasaki disease, Hashimoto's thyroiditis, chronic graft-versus-host disease, acute graft-versus-host disease, Celiac Sprue, idiopathic thrombocytopenic thrombotic purpura, myasthenia gravis, Sjorgren's syndrome, scleroderma, ulcerative colitis, epidermal hyperplasia, glomerulonephritis and amyotrophic lateral sclerosis. In a preferred embodiment, the disease or disorder is rheumatoid arthritis or psoriasis.

The present invention provides novel compounds to be used in the treatment of diseases or disorders associated with the inactivation or activation of the RORy receptor.

Moreover, the present invention describes a method for treating a disease or disorder associated with the modulation of the RORγ receptor, wherein the method comprises administering an effective amount of a compound according to Formula (1) to a subject in need thereof. The disease or disorder is preferably selected from the group consisting of autoimmune diseases such as rheumatoid arthritis, ankylosing spondylitis, lupus erythematosus, psoriasis, atopic eczema, inflammatory bowel diseases such as Crohn's disease, espiratory diseases such as asthma or COPD, infectious diseases such as mucosal leishmaniasis, multiple sclerosis, systemic sclerosis, type 1 diabetes, Kawasaki disease, Hashimoto's thyroiditis, chronic graft-versus-host disease, acute graft-versus-host disease, Celiac Sprue, idiopathic thrombocytopenic thrombotic purpura, myasthenia gravis, Sjorgren's syndrome, scleroderma, ulcerative colitis, epidermal hyperplasia, glomerulonephritis and amyotrophic lateral sclerosis. In a certain embodiment the disorder is rheumatoid arthritis and psoriasis.

The present invention provides a compound represented by Formula (1) an enantiomer, diastereomer, tautomer, N-oxide, solvate, formulation and pharmaceutically acceptable salt thereof,
wherein

• R¹ is selected from H, C_1-10-alkyl, C_2-10-alkenyl, C_2-10-alkynyl, C_3-6-cycloalkyl, C_3-6-heterocycloalkyl, C_1-10-alkylene-C_3-10-cycloalkyl, C_1-10-alkylene-C_3-10-heterocycloalkyl, C_1-10-alkylene-(5-membered monocyclic heteroaryl), SO₂-C_1-10-alkyl, wherein alkyl, alkenyl, alkynyl, alkylene, cycloalkyl, heterocycloalkyl and heteroaryl is unsubstituted or substituted with 1 to 7 substituents independently selected from oxo, CN, OR¹¹, O-C_2-6-alkylene-OR¹¹, C_1-6-alkyl, halo-C_1-6-alkyl, halogen, CO₂R¹¹, CONR¹¹R¹², COR¹¹, SO_yR¹¹, SO₃H, SO₂NR¹¹R¹², NR¹¹COR¹¹, NR¹¹SO₂R¹¹, NR¹¹-CO-NR¹¹R¹², NR¹¹-SO₂-NR¹¹R¹², C_3-6-cycloalkyl, O-C_3-6-cycloalkyl, C_3-6-heterocycloalkyl, O-C_3-6-heterocycloalkyl and NR¹¹R¹²; and
• R³ is pyridinone, a 6- to 10-membered mono- or bicyclic aryl, a 5- to 10-membered mono- or bicyclic heteroaryl containing 1 to 4 heteroatoms independently selected from the group consisting of N, O and S or a 6- to 12-membered partially saturated spiroheterocycle containing 1 to 4 heteroatoms independently selected from the group consisting of N, O and S,
• wherein pyridinone and spiroheterocycle is optionally substituted with 1 to 4 groups independently selected from halogen, C_1-6-alkyl, halo-C_1-6-alkyl, OH, O-C_1-6-alkyl, O-halo-C_1-6-alkyl, oxo, =N-OR³², N(R³²), C_0-6-alkylene-C_3-10-cycloalkyl, C_0-6-alkylene-C_3-10-heterocycloalkyl, C_0-6-alkylene-(5- or 6-membered monocyclic heteroaryl), C_1-6-alkylene-O-R³¹, C_0-6-alkylene-CN, O-C_3-10-cycloalkyl, O-C_1-6-alkylene-O-R³², O-C_3-10-heterocycloalkyl, C_0-6-alkylene-COOR³¹, C_0-6-alkylene-C(O)R³¹, C_0-6-alkylene-C(O)N(R³¹)₂, C_0-6-alkylene-N(R³¹)C(O)R³¹, C_0-6-alkylene-SO-R³¹, C_0-6-alkylene-SO₂-R³¹, C_0-6-alkylene-SO₂-N(R³¹)₂, C_0-6-alkylene-N(R³¹)SO₂-R³¹, C_0-6-alkylene-SO₂-C_3-10-heterocycloalkyl and C_0-6-alkylene-SO₂-C₃-₁₀-heterocycloalkyl,
  wherein alkylene, cycloalkyl, heterocycloalkyl and heteroaryl is optionally substituted by 1 to 4 substituents independently selected from the group consisting of halogen, CN, C_1-3-alkyl, halo-C_1-3-alkyl, OH, oxo, O-C_1-3-alkyl and O-halo-C_1-3-alkyl;
• wherein aryl and heteroaryl is substituted with at least one group selected from C_3-10-cycloalkyl, C₄-heterocycloalkyl, C_1-4-alkylene-C_3-10-cycloalkyl, C_1-4-alkylene-(C_3-10-heterocycloalkyl), C_1-6-alkylene-(5- or 6-membered monocyclic heteroaryl), C_1-4-alkylene-O-R³¹, C_1-4-alkylene-CN, O-C_3-10-cycloalkyl, O-C_1-6-alkylene-O-R³², O-C_3-10-heterocycloalkyl, C_0-6-alkylene-COOR³¹, C_0-6-alkylene-C(O)R³¹, C_0-6-alkylene-C(O)N(R³¹)₂, C_0-6-alkylene-N(R³¹)C(O)R³¹, C_0-6-alkylene-SO-R³¹, C_1-6-alkylene-SO₂-R³¹, C_0-6-alkylene-SO₂-N(R³¹)₂, C_0-6-alkylene-N(R³¹)SO₂-R³¹, SO₂-C_3-10-heterocycloalkyl, SO₂-C_3-10-cycloalkyl, C_0-6-alkylene-SO-R³¹ and two adjacent substituents completing a 3- to 8-membered saturated or partially unsaturated ring containing carbon atoms and optionally containing 1 to 3 heteroatoms selected from O, S or N, wherein the ring is unsubstituted or substituted with 1 to 6 substituents independently selected from halogen, C_1-6-alkyl, halo-C_1-6-alkyl, C_3-6-cycloalkyl, C_3-6-heterocycloalkyl, oxo, =N-OR³², OH, O-C_1-6-alkyl and O-halo-C_1-6-alkyl,
  wherein alkylene, cycloalkyl, heterocycloalkyl and the 5- or 6-membered monocyclic heteroaryl is optionally substituted by 1 to 4 substituents independently selected from the group consisting of halogen, CN, C_1-3-alkyl, halo-C_1-3-alkyl, OH, oxo, =N-OR³², O-C_1-3-alkyl and O-halo-C_1-3-alkyl; and
• wherein aryl and heteroaryl are optionally substituted by 1 to 4 substituents independently selected from the group consisting of halogen, CN, C_1-3-alkyl, halo-C_1-3-alkyl, OH, O-C_1-3-alkyl and O-halo-C_1-3-alkyl;
  or
• R¹ is selected from
• a 4-membered heterocycloalkyl group containing one heteroatom selected from the group consisting of N, O and S, or
• C_1-10-alkyl substituted with a group selected from halogen, CN, OR¹¹, SO_yR¹¹, SO₃H, NR¹¹SO₂R¹¹, SO₂NR¹¹R¹², CO₂R¹¹, CONR¹¹R¹², NR¹¹-CO-R¹¹, NR¹¹-CO-NR¹¹R¹², NR¹¹-SO₂-NR¹¹R¹², NR¹¹R¹² and a 4-membered heterocycloalkyl group containing one heteroatom selected from the group consisting of N, O and S, or
• C_0-1-alkylene-C_3-10-cycloalkyl substituted with a group selected from halogen, CN, SO_yR¹¹, NR¹¹SO₂R¹¹, SO₂NR¹¹R¹², CO₂R¹¹, CONR¹¹R¹², NR¹¹-CO-R¹¹, NR¹¹-CO-NR¹¹R¹², NR¹¹-SO₂-NR¹¹R¹² and NR¹¹R¹², or
• C_2-10-alkylene-C_3-10-cycloalkyl, C_2-10-alkylene-O-C_3-10-cycloalkyl, C_2-10-alkylene-C_5-10-heterocycloalkyl, C_2-10-alkylene-O-C_5-10-heterocycloalkyl and SO₂-C_1-10-alkyl,
• wherein alkyl, alkylene, cycloalkyl and heterocycloalkyl are optionally substituted with 1 to 7 substituents independently selected from the group consisting of OH, oxo, CN, O-C_1-6-alkyl, O-halo-C_1-6-alkyl, C_1-6-alkyl, halo-C_1-6-alkyl, halogen, CO₂R¹¹, CONR¹¹R¹², COR¹¹, SO₂R¹¹, SO₂NR¹¹R¹², NR¹¹COR¹¹, NR¹¹SO₂R¹¹, C_3-6-cycloalkyl, O-C_3-6-cycloalkyl, C_3-6-heterocycloalkyl, O-C_3-6-heterocycloalkyl, O-C_2-6-alkylene-OR¹¹ and NR¹¹R¹²; and
• R³ is pyridinone, a 6- to 10-membered mono- or bicyclic aryl, a 5- to 10-membered mono- or bicyclic heteroaryl containing 1 to 4 heteroatoms independently selected from the group consisting of N, O and S or a 6- to 12-membered partially saturated spiroheterocycle containing 1 to 4 heteroatoms independently selected from the group consisting of N, O and S,
• wherein pyridinone, aryl and heteroaryl and spiroheterocycle is optionally substituted with 1 to 4 groups independently selected from halogen, C_1-6-alkyl, halo-C_1-6-alkyl, OH, O-C_1-6-alkyl, O-halo-C_1-6-alkyl, oxo, =N-OR³², N(R³²), C_0-6-alkylene-C_3-10-cycloalkyl, C_0-6-alkylene-C_3-10-heterocycloalkyl, C_0-6-alkylene-(5- or 6-membered monocyclic heteroaryl), C_1-6-alkylene-O-R³¹, C_0-6-alkylene-CN, O-C_3-10-cycloalkyl, O-C_1-6-alkylene-O-R³², O-C_3-10-heterocycloalkyl, C_0-6-alkylene-COOR³¹, C_0-6-alkylene-C(O)R³¹, C_0-6-alkylene-C(O)N(R³¹)₂, C_0-6-alkylene-N(R³¹)C(O)R³¹, C_0-6-alkylene-SO-R³¹, C_0-6-alkylene-SO₂-R³¹, C_0-6-alkylene-SO₂-N(R³¹)₂ and C_0-6-alkylene-N(R³¹)SO₂-R³¹, and two adjacent substituents completing a 3- to 8-membered saturated or partially unsaturated ring containing carbon atoms and optionally containing 1 to 3 heteroatoms selected from O, S or N, wherein the ring is unsubstituted or substituted with 1 to 6 substituents independently selected from halogen, C_1-6-alkyl, halo-C_1-6-alkyl, C_3-6-cycloalkyl, C_3-6-heterocycloalkyl, oxo, =N-OR³², OH, O-C_1-6-alkyl and O-halo-C_1-6-alkyl,
  wherein alkylene, cycloalkyl, heterocycloalkyl and the 5- or 6-membered monocyclic heteroaryl is optionally substituted by 1 to 4 substituents independently selected from the group consisting of halogen, CN, C_1-3-alkyl, halo-C_1-3-alkyl, OH, oxo, =N-OR³², O-C_1-3-alkyl and O-halo-C_1-3-alkyl;
  and
• R² is selected from the group consisting of H, C_1-6-alkyl, halo-C_1-6-alkyl and hydroxy-C_1-6-alkyl,
• or R¹ and R² when taken together with the nitrogen to which they are attached complete a 3-to 8-membered ring containing carbon atoms and optionally containing 1 or 2 heteroatoms selected from O, S or N, wherein the ring is unsubstituted or substituted with 1 to 4 substitutents independently selected from halogen, oxo, CN, OR¹¹, SO_yR¹¹, SO₃H, NR¹¹SO₂R¹¹, SO₂NR¹¹R¹², C_0-6-alkylene-CO₂R¹¹, CONR¹¹R¹², COR¹¹, NR¹¹-CO-R¹¹, NR¹¹-CO-NR¹¹R¹², NR¹¹-SO₂-NR¹¹R¹², NR¹¹R¹², C_1-6-alkyl, halo-C_1-6-alkyl, hydroxy-C_1-6-alkyl, C_3-6-cycloalkyl, O-C_3-6-cycloalkyl, C_3-6-heterocycloalkyl and O-C_3-6-heterocycloalkyl,
  wherein cycloalkyl and heterocycloalkyl are unsubstituted or substituted with 1 to 4 substitutents independently selected from halogen, C_1-3-alkyl, halo-C_1-3-alkyl and oxo;
• R⁴ is SO₂-(CR⁸R⁸)_yR⁷, SO₂-NR¹²R⁷, (CR⁸R⁸)_x-R¹⁰ or C_3-6-cycloalkyl, which is spirocyclic fused with C_3-10-cycloalkyl;
• R⁵ is selected from H, C_1-6-alkyl, halo-C_1-6-alkyl, CHO, CON(R⁵²)₂ or halogen, wherein alkyl is unsubstituted or substituted with 1 to 3 substituents independently selected from the group consisting of O-C_1-6-alkyl, O-halo-C_1-6-alkyl and OH;
• R⁶ is selected from H, C_1-6-alkyl, halo-C_1-6-alkyl or halogen;
• R⁷ is selected from C_3-10-cycloalkyl and C_3-10-heterocycloalkyl,
  wherein cycloalkyl and heterocycloalkyl are unsubstituted or substituted with 1 to 3 substituents independently selected from the group consisting of halogen, OH, oxo, O-C_1-6-alkyl, O-halo-C_1-6-alkyl, C_1-6-alkyl, halo-C_1-6-alkyl, cycloalkyl and heterocycloalkyl;
• R⁸ is independently selected from H, F, C_1-3-alkyl, halo-C_1-3-alkyl or OH;
• R¹⁰ is C_3-10-cycloalkyl, wherein cycloalkyl is unsubstituted or substituted with 1 to 6 substituents independently selected from halogen, OH, oxo, O-C_1-6-alkyl, O-halo-C_1-6-alkyl, C_1-6-alkyl, halo-C_1-6-alkyl, cycloalkyl, heterocycloalkyl, and optionally two adjacent substituents together complete a 6-membered aryl ring wherein the ring is unsubstituted or substituted with 1 to 3 substituents independently selected from halogen, C_1-2-alkyl, halo-C_1-2-alkyl;
• R¹¹ is independently selected from H, C_1-6-alkyl, C_0-6-alkylene-C_3-6-cycloalkyl, C_0-6-alkylene-C_3-6-heterocycloalkyl, wherein alkyl, alkylene, cyclolalkyl and heterocycloalkyl are unsubstituted or substituted with 1 to 6 substituents independently selected from halogen, OH, oxo, C_1-3-alkyl, halo-C_1-3-alkyl, O-C_1-3-alkyl, O-halo-C_1-3-alkyl and SO₂-C_1-3-alkyl;
• R¹² is independently selected from H, C_1-6-alkyl and halo-C_1-6-alkyl;
• R³¹ is independently selected from H, C_1-6-alkyl, halo-C_1-6-alkyl, C_0-6-alkylene-C_3-6-cycloalkyl, C_0-6-alkylene-C_3-6-heterocycloalkyl, 5- or 6-membered heteroaryl and 6-membered aryl, wherein alkyl, alkylene, cyclolalkyl, heterocycloalkyl, aryl and heteroaryl are unsubstituted or substituted with 1 to 6 substituents independently selected from halogen, CN, OH, oxo, C_1-3-alkyl, halo-C_1-3-alkyl, O-C_1-3-alkyl, O-halo-C_1-3-alkyl and SO₂-C_1-3-alkyl;
• and optionally wherein two R³¹ when taken together with the nitrogen to which they are attached complete a 3- to 8-membered ring containing carbon atoms and optionally containing 1 or 2 heteroatoms selected from O, S or N, wherein the ring is unsubstituted or substituted with 1 to 4 substitutents independently selected from fluoro, OH, oxo, C_1-4-alkyl and halo-C_1-4-alkyl;
• R³² is independently selected from H, C_1-6-alkyl and halo-C_1-6-alkyl;
• R⁵² is independently selected from H, C_1-3-alkyl and halo-C_1-3-alkyl;
• x is independently selected from 1 and 2;
• y is independently selected from 0, 1 and 2;
• with the proviso that R³ is not an unsubstituted or substituted ring selected from

In a prefered embodiment, the present invention provides a compound of Formula (1) an enantiomer, diastereomer, tautomer, solvate, formulation and pharmaceutically acceptable salt thereof,
wherein

• R¹ is selected from H, C_1-10-alkyl, C_2-10-alkenyl, C_2-10-alkynyl, C_3-6-cycloalkyl, C_3-6-heterocycloalkyl, C_1-10-alkylene-C_3-10-cycloalkyl, C_1-10-alkylene-C_3-10-heterocycloalkyl, C_1-10-alkylene-(5-membered monocyclic heteroaryl), SO₂-C_1-10-alkyl, wherein alkyl, alkenyl, alkynyl, alkylene, cycloalkyl, heterocycloalkyl and heteroaryl is unsubstituted or substituted with 1 to 7 substituents independently selected from oxo, CN, OR¹¹, O-C_2-6-alkylene-OR¹¹, C_1-6-alkyl, halo-C_1-6-alkyl, halogen, CO₂R¹¹, CONR¹¹R¹², COR¹¹, SO_yR¹¹, SO₃H, SO₂NR¹¹R¹², NR¹¹COR¹¹, NR¹¹SO₂R¹¹, NR¹¹-CO-NR¹¹R¹², NR¹¹-SO₂-NR¹¹R¹², C_3-6-cycloalkyl, O-C_3-6-cycloalkyl, C_3-6-heterocycloalkyl, O-C_3-8-heterocycloalkyl and NR¹¹R¹²; and
• R³ is pyridinone, a 6- to 10-membered mono- or bicyclic aryl, a 5- to 10-membered mono- or bicyclic heteroaryl containing 1 to 4 heteroatoms independently selected from the group consisting of N, O and S or a 6- to 12-membered partially saturated spiroheterocycle containing 1 to 4 heteroatoms independently selected from the group consisting of N, O and S,
• wherein pyridinone and spiroheterocycle is optionally substituted with a group selected from C_3-10-cycloalkyl, C₄-heterocycloalkyl, C_1-4-alkylene-C_3-10-cycloalkyl, C_1-4-alkylene-C_3-10-heterocycloalkyl, C_0-6-alkylene-(5-membered monocyclic heteroaryl), C_1-4-alkylene-O-R³¹, C_1-4-alkylene-CN, O-C_3-10-cycloalkyl, O-C_1-6-alkylene-O-R³², O-C_3-10-heterocycloalkyl, C_0-6-alkylene-COOR³¹, C_0-6-alkylene-C(O)R³¹, C_0-6-alkylene-C(O)N(R³¹)₂, C_0-6-alkylene-N(R³¹)C(O)R³¹, C_0-6-alkylene-SO₂-N(R³¹)₂, C_0-6-alkylene-N(R³¹)SO₂-R³¹, C_0-6-alkylene-SO₂-C_3-10-heterocycloalkyl and C_0-6-alkylene-SO-R³¹,
• aryl and heteroaryl is substituted with at least one group selected from C_3-10-cycloalkyl, C₄-heterocycloalkyl, C_1-4-alkylene-C_3-10-cycloalkyl, C_1-4-alkylene-C_3-10-heterocycloalkyl, C_1-4-alkylene-O-R³¹, C_1-4-alkylene-CN, O-C_3-10-cycloalkyl, O-C_1-6-alkylene-O-R³², O-C_3-10-heterocycloalkyl, C_0-6-alkylene-COOR³¹, C_0-6-alkylene-C(O)R³¹, C_0-6-alkylene-C(O)N(R³¹)₂, C_0-6-alkylene-N(R³¹)C(O)R³¹, C_0-6-alkylene-SO₂-N(R³¹)₂, C_0-6-alkylene-N(R³¹)SO₂-R³¹, C_0-6-alkylene-SO₂-C_3-10-heterocycloalkyl, C_0-6-alkylene-SO-R³¹ and two adjacent substituents completing a 3- to 8-membered saturated or partially unsaturated ring containing carbon atoms and optionally containing 1 to 3 heteroatoms selected from O, S or N, wherein the ring is unsubstituted or substituted with 1 to 6 substituents independently selected from halogen, C_1-6-alkyl, halo-C_1-6-alkyl, C_3-6-cycloalkyl, C_3-6-heterocycloalkyl, oxo, OH, O-C_1-6-alkyl and O-halo-C_1-6-alkyl,
  wherein pyridinone, aryl, heteroaryl, spiroheterocycle, alkyl, alkylene, cycloalkyl and heterocycloalkyl are optionally substituted by 1 to 4 substituents independently selected from the group consisting of halogen, CN, C_1-6-alkyl, halo-C_1-6-alkyl, C_3-6-cycloalkyl, C_3-6-heterocycloalkyl, OH, O-C_1-3-alkyl, O-halo-C_1-3-alkyl, O-C_3-6-cycloalkyl, O-C_3-6-heterocycloalkyl, oxo, N(R³²)₂, COOH, CON(R³²)₂, CN and NR³²-COR³²;
  or
• R¹ is selected from
• a 4-membered heterocycloalkyl group containing one heteroatom selected from the group consisting of N, O and S, or
• C_1-10-alkyl substituted with a group selected from halogen, CN, OR¹¹, SO_yR¹¹, SO₃H, NR¹¹SO₂R¹¹, SO₂NR¹¹R¹², CO₂R¹¹, CONR¹¹R¹², NR¹¹-CO-R¹¹, NR¹¹-CO-NR¹¹R¹², NR¹¹-SO₂-NR¹¹R¹², NR¹¹R¹² and a 4-membered heterocycloalkyl group containing one heteroatom selected from the group consisting of N, O and S, or
• C_0-1-alkylene-C_3-10-cycloalkyl substituted with a group selected from halogen, CN, SO_yR¹¹, NR¹¹SO₂R¹¹, SO₂NR¹¹R¹², CO₂R¹¹, CONR¹¹R¹², NR¹¹-CO-R¹¹, NR¹¹-CO-NR¹¹R¹², NR¹¹-SO₂-NR¹¹R¹² and NR¹¹R¹², or
• C_2-10-alkylene-C_3-10-cycloalkyl, C_2-10-alkylene-O-C_3-10-cycloalkyl, C_2-10-alkylene-C_5-10-heterocycloalkyl, C_2-10-alkylene-O-C_5-10-heterocycloalkyl and SO₂-C_1-10-alkyl,
• wherein alkyl, alkylene, cycloalkyl and heterocycloalkyl are optionally substituted with 1 to 7 substituents independently selected from the group consisting of OH, oxo, CN, O-C_1-6-alkyl, O-halo-C_1-6-alkyl, C_1-6-alkyl, halo-C_1-6-alkyl, halogen, CO₂R¹¹, CONR¹¹R¹², COR¹¹, SO₂R¹¹, SO₂NR¹¹R¹², NR¹¹COR¹¹, NR¹¹SO₂R¹¹, C_3-6-cycloalkyl, O-C_3-6-cycloalkyl, C_3-6-heterocycloalkyl, O-C_3-6-heterocycloalkyl, O-C_2-6-alkylene-OR¹¹ and NR¹¹R¹²; and
• R³ is pyridinone, a 6- to 10-membered mono- or bicyclic aryl, a 5- to 10-membered mono- or bicyclic heteroaryl containing 1 to 4 heteroatoms independently selected from the group consisting of N, O and S or a 6- to 12-membered partially saturated spiroheterocycle containing 1 to 4 heteroatoms independently selected from the group consisting of N, O and S,
• wherein pyridinone, aryl, heteroaryl and spiroheterocycle are unsubstituted or substituted with 1 to 5 substituents independently selected from halogen, CN, C_1-6-alkyl, C_3-10-cycloalkyl, C_3-10-heterocycloalkyl, C_0-6-alkylene-(5-membered monocyclic heteroaryl), C_0-6-alkylene-(6-membered monocyclic heteroaryl), C_0-6-alkylene-O-R³¹, O-C_1-6-alkylene-O-R³², C_0-6-alkylene-COOR³¹, C_0-6-alkylene-C(O)R³¹, C_0-6-alkylene-C(O)N(R³¹)₂, C_0-6-alkylene-N(R³¹)C(O)R³¹, C_0-6-alkylene-SO₂-N(R³¹)₂, C_0-6-alkylene-N(R³¹)SO₂-R³¹, C_0-6-alkylene-SO₂-R³¹, C_0-6-alkylene-SO-R³¹ and C_0-6-alkylene-N(R³¹)₂,
  wherein alkyl, alkylene, cycloalkyl and heterocycloalkyl are unsubstituted or substituted by 1 to 4 substituents independently selected from the group consisting of halogen, CN, C_1-3-alkyl, halo-C_1-6-alkyl, C_3-6-cycloalkyl, C_3-6-heterocycloalkyl, OH, O-C_1-3-alkyl, O-halo-C_1-3-alkyl, O-C_3-6-cycloalkyl, O-C_3-6-heterocycloalkyl, oxo, N(R³²)₂, COOH, CON(R³²)₂, CN and NR³²-COR³²,
• and wherein optionally two adjacent substituents complete a 3- to 8-membered saturated or partially unsaturated ring containing carbon atoms and optionally containing 1 to 3 heteroatoms selected from O, S or N, wherein the ring is unsubstituted or substituted with 1 to 6 substituents independently selected from halogen, C_1-6-alkyl, halo-C_1-6-alkyl, C_3-6-cycloalkyl, C_3-6-heterocycloalkyl, oxo, OH, O-C_1-6-alkyl and O-halo-C_1-6-alkyl;
  and
• R² is selected from the group consisting of H, C_1-6-alkyl, halo-C_1-6-alkyl and hydroxy-C_1-6-alkyl,
• or R¹ and R² when taken together with the nitrogen to which they are attached complete a 3-to 8-membered ring containing carbon atoms and optionally containing 1 or 2 heteroatoms selected from O, S or N, wherein the ring is unsubstituted or substituted with 1 to 4 substitutents independently selected from halogen, oxo, CN, OR¹¹, SO_yR¹¹, SO₃H, NR¹¹SO₂R¹¹, SO₂NR¹¹R¹², CO₂R¹¹, CONR¹¹R¹², COR¹¹, NR¹¹-CO-R¹¹, NR¹¹-CO-NR¹¹R¹², NR¹¹-SO₂-NR¹¹R¹², NR¹¹R¹², C_1-6-alkyl, halo-C_1-6-alkyl, hydroxy-C_1-6-alkyl, C_3-6-cycloalkyl, O-C_3-6-cycloalkyl, C_3-6-heterocycloalkyl and O-C_3-6-heterocycloalkyl;
• R⁴ is SO₂-(CR⁸R⁸)_yR⁷, SO₂-NR¹²R⁷ or (CR⁸R⁸)_x-R¹⁰;
• R⁵ is selected from H, C_1-6-alkyl, halo-C_1-6-alkyl, CHO or halogen, wherein alkyl is unsubstituted or substituted with 1 to 3 substituents independently selected from the group consisting of O-C_1-6-alkyl, O-halo-C_1-6-alkyl and OH;
• R⁶ is selected from H, C_1-6-alkyl, halo-C_1-6-alkyl or halogen;
• R⁷ is selected from C_3-10-cycloalkyl and C_3-10-heterocycloalkyl,
  wherein cycloalkyl and heterocycloalkyl are unsubstituted or substituted with 1 to 3 substituents independently selected from the group consisting of halogen, OH, oxo, O-C_1-6-alkyl, O-halo-C_1-6-alkyl, C_1-6-alkyl, halo-C_1-6-alkyl, cycloalkyl and heterocycloalkyl;
• R⁸ is independently selected from H, F, C_1-3-alkyl, halo-C_1-3-alkyl or OH;
• R¹⁰ is C_3-10-cycloalkyl, wherein cycloalkyl is unsubstituted or substituted with 1 to 6 substituents independently selected from halogen, OH, oxo, O-C_1-6-alkyl, O-halo-C_1-6-alkyl, C_1-6-alkyl, halo-C_1-6-alkyl, cycloalkyl, heterocycloalkyl, and optionally two adjacent substituents together complete a 6-membered aryl ring wherein the ring is unsubstituted or substituted with 1 to 3 substituents independently selected from halogen, C_1-2-alkyl, halo-C_1-2-alkyl;
• R¹¹ is independently selected from H, C_1-6-alkyl, C_0-6-alkylene-C_3-6-cycloalkyl, C_0-6-alkylene-C_3-6-heterocycloalkyl, wherein alkyl, alkylene, cyclolalkyl and heterocycloalkyl are unsubstituted or substituted with 1 to 6 substituents independently selected from halogen, OH, oxo, C_1-3-alkyl, halo-C_1-3-alkyl, O-C_1-3-alkyl, O-halo-C_1-3-alkyl and SO₂-C_1-3-alkyl;
• R¹² is independently selected from H, C_1-6-alkyl and halo-C_1-6-alkyl;
• R³¹ is independently selected from H, C_1-6-alkyl, C_0-6-alkylene-C_3-6-cycloalkyl, C_0-6-alkylene-C_3-6-heterocycloalkyl, a 6-membered aryl wherein alkyl, alkylene, cyclolalkyl, heterocycloalkyl and aryl are unsubstituted or substituted with 1 to 6 substituents independently selected from halogen, OH, oxo, C_1-3-alkyl, halo-C_1-3-alkyl, O-C_1-3-alkyl, O-halo-C_1-3-alkyl and SO₂-C_1-3-alkyl;
• R³² is independently selected from H, C_1-6-alkyl and halo-C_1-6-alkyl;
• x is independently selected from 1 and 2;
• y is independently selected from 0, 1 and 2;
• with the proviso that R³ is not an unsubstituted or substituted ring selected from

In a first alternative, the invention provides a compound represented by Formula (1) an enantiomer, diastereomer, tautomer, N-oxide, solvate, formulation and pharmaceutically acceptable salt thereof,
wherein

• R¹ is selected from H, C_1-10-alkyl, C_3-6-cycloalkyl, C_3-6-heterocycloalkyl, C_1-10-alkylene-C_3-10-cycloalkyl, C_1-10-alkylene-C_3-10-heterocycloalkyl, C_1-10-alkylene-(5-membered monocyclic heteroaryl), wherein alkyl, alkylene, cycloalkyl, heterocycloalkyl and heteroaryl is unsubstituted or substituted with 1 to 7 substituents independently selected from oxo, CN, OR¹¹, O-C_2-6-alkylene-OR¹¹, C_1-6-alkyl, halo-C_1-6-alkyl, halogen, CO₂R¹¹, CONR¹¹R¹², COR¹¹, SO_yR¹¹, SO₃H, SO₂NR¹¹R¹², NR¹¹COR¹¹, NR¹¹SO₂R¹¹, NR¹¹-CO-NR¹¹R¹², NR¹¹-SO₂-NR¹¹R¹², C_3-6-cycloalkyl, O-C_3-6-cycloalkyl, C_3-6-heterocycloalkyl, O-C_3-6-heterocycloalkyl and NR¹¹R¹²;
• R² is selected from the group consisting of H, C_1-6-alkyl, halo-C_1-6-alkyl and hydroxy-C_1-6-alkyl,
• or R¹ and R² when taken together with the nitrogen to which they are attached complete a 3-to 8-membered ring containing carbon atoms and optionally containing 1 or 2 heteroatoms selected from O, S or N, wherein the ring is unsubstituted or substituted with 1 to 4 substitutents independently selected from halogen, oxo, CN, OR¹¹, SO_yR¹¹, SO₃H, NR¹¹SO₂R¹¹, SO₂NR¹¹R¹², C_0-6-alkylene-CO₂R¹¹, CONR¹¹R¹², COR¹¹, NR¹¹-CO-R¹¹, NR¹¹-CO-NR¹¹R¹², NR¹¹-SO₂-NR¹¹R¹², NR¹¹R¹², C_1-6-alkyl, halo-C_1-6-alkyl, hydroxy-C_1-6-alkyl, C_3-6-cycloalkyl, O-C_3-6-cycloalkyl, C_3-6-heterocycloalkyl and O-C_3-6-heterocycloalkyl,
  wherein cycloalkyl and heterocycloalkyl are unsubstituted or substituted with 1 to 4 substitutents independently selected from halogen, C_1-3-alkyl, halo-C_1-3-alkyl and oxo;
• R³ is a 6- or 10-membered mono- or bicyclic aryl or a 6- to 10-membered mono- or bicyclic heteroaryl containing 1 or 2 heteroatoms selected from the group consisting of N, O and S,
• wherein aryl and heteroaryl is substituted with at least one group selected from C_3-6-cycloalkyl, C₄-heterocycloalkyl, C_1-4-alkylene-C_3-10-cycloalkyl, C_1-4-alkylene-O-R³¹, O-C_3-10-cycloalkyl, C(O)R³¹, C_0-6-alkylene-C(O)N(R³¹)₂, SO₂-N(R³¹)₂, N(R³¹)SO₂-R³¹, SO₂-C_3-10-heterocycloalkyl, SO-R³¹ and two adjacent substituents completing a 3- to 8-membered saturated or partially unsaturated ring containing carbon atoms and optionally containing 1 to 3 heteroatoms selected from O, S or N, wherein the ring is unsubstituted or substituted with 1 to 6 substituents independently selected from halogen, C_1-6-alkyl, halo-C_1-6-alkyl, C_3-6-cycloalkyl, C_3-6-heterocycloalkyl, oxo, =N-OR³², OH, O-C_1-6-alkyl and O-halo-C_1-6-alkyl,
  wherein alkylene, cycloalkyl, heterocycloalkyl and the carbon atom linked 5- or 6-membered monocyclic heteroaryl is optionally substituted by 1 to 4 substituents independently selected from the group consisting of halogen, CN, C_1-3-alkyl, halo-C_1-3-alkyl, OH, oxo, =N-OR³², O-C_1-3-alkyl and O-halo-C_1-3-alkyl; and
• wherein aryl and heteroaryl are optionally substituted by 1 to 4 substituents independently selected from the group consisting of halogen, CN, C_1-3-alkyl, halo-C_1-3-alkyl, OH, O-C_1-3-alkyl and O-halo-C_1-3-alkyl; and
• R⁴ is SO₂-(CR⁸R⁸)_yR⁷, SO₂-NR¹²R⁷, (CR⁸R⁸)_x-R¹⁰ or C_3-6-cycloalkyl, which is spirocyclic fused with C_3-10-cycloalkyl;
• R⁵ is selected from H, C_1-6-alkyl, halo-C_1-6-alkyl, CHO, CON(R⁵²)₂ or halogen, wherein alkyl is unsubstituted or substituted with 1 to 3 substituents independently selected from the group consisting of O-C_1-6-alkyl, O-halo-C_1-6-alkyl and OH;
• R⁶ is selected from H, C_1-6-alkyl, halo-C_1-6-alkyl or halogen;
• R⁷ is selected from C_3-10-cycloalkyl and C_3-10-heterocycloalkyl,
  wherein cycloalkyl and heterocycloalkyl are unsubstituted or substituted with 1 to 3 substituents independently selected from the group consisting of halogen, OH, oxo, O-C_1-6-alkyl, O-halo-C_1-6-alkyl, C_1-6-alkyl, halo-C_1-6-alkyl, cycloalkyl and heterocycloalkyl;
• R⁸ is independently selected from H, F, C_1-3-alkyl, halo-C_1-3-alkyl or OH;
• R¹⁰ is C_3-10-cycloalkyl, wherein cycloalkyl is unsubstituted or substituted with 1 to 6 substituents independently selected from halogen, OH, oxo, O-C_1-6-alkyl, O-halo-C_1-6-alkyl, C_1-6-alkyl, halo-C_1-6-alkyl, cycloalkyl, heterocycloalkyl, and optionally two adjacent substituents together complete a 6-membered aryl ring wherein the ring is unsubstituted or substituted with 1 to 3 substituents independently selected from halogen, C_1-2-alkyl, halo-C_1-2-alkyl;
• R¹¹ is independently selected from H, C_1-6-alkyl, C_0-6-alkylene-C_3-6-cycloalkyl, C_0-6-alkylene-C_3-6-heterocycloalkyl, wherein alkyl, alkylene, cyclolalkyl and heterocycloalkyl are unsubstituted or substituted with 1 to 6 substituents independently selected from halogen, OH, oxo, C_1-3-alkyl, halo-C_1-6-alkyl, O-C_1-3-alkyl, O-halo-C_1-3-alkyl and SO₂-C_1-3-alkyl;
• R¹² is independently selected from H, C_1-6-alkyl and halo-C_1-6-alkyl;
• R³¹ is independently selected from H, C_1-6-alkyl, halo-C_1-6-alkyl, C_0-6-alkylene-C_3-6-cycloalkyl, C_0-6-alkylene-C_3-6-heterocycloalkyl, 5- or 6-membered heteroaryl and 6-membered aryl, wherein alkyl, alkylene, cyclolalkyl, heterocycloalkyl, aryl and heteroaryl are unsubstituted or substituted with 1 to 6 substituents independently selected from halogen, CN, OH, oxo, C_1-3-alkyl, halo-C_1-3-alkyl, O-C_1-3-alkyl, O-halo-C_1-3-alkyl and SO₂-C_1-3-alkyl;
• and optionally wherein two R³¹ when taken together with the nitrogen to which they are attached complete a 3- to 8-membered ring containing carbon atoms and optionally containing 1 or 2 heteroatoms selected from O, S or N, wherein the ring is unsubstituted or substituted with 1 to 4 substitutents independently selected from fluoro, OH, oxo, C_1-4-alkyl and halo-C_1-4-alkyl;
• R³² is independently selected from H, C_1-6-alkyl and halo-C_1-6-alkyl;
• R⁵² is independently selected from H, C_1-3-alkyl and halo-C_1-3-alkyl;
• x is independently selected from 1 and 2;
• y is independently selected from 0, 1 and 2.

In an additionally preferred embodiment in combination with any of the above or below embodiments of the first alternative R³ is selected from phenyl, pyridinyl, pyrimidinyl, naphthyl, benzothiophenyl and quinolinyl, wherein phenyl, pyridinyl, pyrimidinyl, naphthyl, benzothiophenyl and quinolinyl is substituted with at least one group selected from C_3-4-cycloalkyl, C_1-4-alkylene-O-R³¹, C(O)R³¹, C(O)N(R³¹)₂, SO₂-N(R³¹)₂, SO₂-C_3-10-heterocycloalkyl, SO-R³¹ and two adjacent substituents completing a 3- to 8-membered saturated or partially unsaturated ring containing carbon atoms and optionally containing 1 to 3 heteroatoms selected from O, S or N, wherein the ring is unsubstituted or substituted with 1 to 5 substituents independently selected from halogen, C_1-3-alkyl, halo-C_1-3-alkyl, C_3-4-cycloalkyl, C_3-4-heterocycloalkyl, oxo, OH, O-C_1-3-alkyl and O-halo-C_1-3-alkyl,
wherein phenyl, pyridinyl, pyrimidinyl, naphthyl, benzothiophenyl, chinolinyl, alkyl, alkylene, cycloalkyl, heterocycloalkyl and the carbon atom linked 5- or 6-membered monocyclic heteroaryl are optionally substituted by 1 to 4 substituents independently selected from the group consisting of halogen, CN, C_1-3-alkyl, halo-C_1-3-alkyl, OH, O-C_1-3-alkyl and O-halo-C_1-3-alkyl.

In a further preferred embodiment in combination with any of the above or below embodiments of the first alternative R¹ is selected from C_1-10-alkyl, C_3-6-cycloalkyl, C_3-6-heterocycloalkyl, C_1-10-alkylene-C_3-10-cycloalkyl, C_1-10-alkylene-C_3-10-heterocycloalkyl, wherein alkyl, alkylene, cycloalkyl and heterocycloalkyl is unsubstituted or substituted with 1 to 7 substituents independently selected from oxo, CN, OR¹¹, O-C_2-6-alkylene-OR¹¹, C_1-6-alkyl, halo-C_1-6-alkyl, halogen, CO₂R¹¹, CONR¹¹R¹², COR¹¹, SO_yR¹¹, SO₃H, SO₂NR¹¹R¹², NR¹¹COR¹¹, NR¹¹SO₂R¹¹, NR¹¹-CO-NR¹¹R¹², NR¹¹-SO₂-NR¹¹R¹², C_3-6-cycloalkyl, O-C_3-6-cycloalkyl, C_3-6-heterocycloalkyl, O-C_3-6-heterocycloalkyl and NR¹¹R¹²;
R² is selected from the group consisting of H, C_1-6-alkyl and halo-Ci-e-alkyl,
or R¹ and R² when taken together with the nitrogen to which they are attached complete a 3-to 8-membered ring containing carbon atoms and optionally containing 1 or 2 heteroatoms selected from O, S or N, wherein the ring is unsubstituted or substituted with 1 to 4 substituents independently selected from halogen, oxo, CN, OR¹¹, SO_yR¹¹, SO₃H, NR¹¹SO₂R¹¹, SO₂NR¹¹R¹², C_0-6-alkylene-CO₂R¹¹, CONR¹¹R¹², COR¹¹, NR¹¹-CO-R¹¹, NR¹¹-CO-NR¹¹R¹², NR¹¹-SO₂-NR¹¹R¹², NR¹¹R¹², C_1-6-alkyl, halo-C_1-6-alkyl, hydroxy-C_1-6-alkyl, C_3-6-cycloalkyl, O-C_3-6-cycloalkyl, C_3-6-heterocycloalkyl and O-C_3-6-heterocycloalkyl,
wherein cycloalkyl and heterocycloalkyl are unsubstituted or substituted with 1 to 4 substituents independently selected from halogen, C_1-3-alkyl, halo-C_1-3-alkyl and oxo.

In an additionally preferred embodiment in combination with any of the above or below embodiments of the first alternative R¹ is selected from C_1-10-alkyl, C_3-6-cycloalkyl, C_3-6-heterocycloalkyl, C_1-10-alkylene-C_3-10-cycloalkyl, more preferably C_1-3-alkylene-C_3-10-cycloalkyl, C_1-10-alkylene-C_3-6-heterocycloalkyl, more preferably C_1-3-alkylene-C_3-6-heterocycloalkyl, wherein alkyl, alkylene, cycloalkyl and heterocycloalkyl is unsubstituted or substituted with 1 to 7 substituents independently selected from oxo, CN, OR¹¹, O-C_2-6-alkylene-OR¹¹, C_1-6-alkyl, halo-C_1-6-alkyl, halogen, CO₂H, CONR¹¹R¹², COR¹¹, SO_yR¹¹, SO₃H, SO₂NR¹¹R¹², NR¹¹COR¹¹, NR¹¹SO₂R¹¹, NR¹¹-CO-NR¹¹R¹², NR¹¹-SO₂-NR¹¹R¹², C_3-6 cycloalkyl, O-C_3-6-cycloalkyl, C_3-6-heterocycloalkyl, O-C_3-6-heterocycloalkyl and NR¹¹R¹²;
R² is selected from the group consisting of H, C_1-6-alkyl and halo-C_1-6-alkyl, more preferably R² is hydrogen;
or R¹ and R² when taken together with the nitrogen to which they are attached complete a 3-to 6-membered ring containing carbon atoms and optionally containing 1 or 2 heteroatoms selected from O, S or N, wherein the ring is unsubstituted or substituted with 1 to 4 substitutents independently selected from halogen, oxo, CN, OR¹¹, SO_yR¹¹, SO₃H, NR¹¹SO₂R¹¹, SO₂NR¹¹R¹², CMe₂CO₂H, CONR¹¹R¹², COR¹¹, NR¹¹-CO-R¹¹, NR¹¹-CO-NR¹¹R¹², NR¹¹-SO₂-NR¹¹R¹², NR¹¹R¹², C_1-6-alkyl, halo-C_1-6-alkyl, hydroxy-C_1-6-alkyl, C_3-6-cycloalkyl, O-C_3-6-cycloalkyl, C_3-6-heterocycloalkyl and O-C_3-6-heterocycloalkyl, wherein cycloalkyl and heterocycloalkyl are unsubstituted or substituted with 1 to 4 substitutents independently selected from halogen, C_1-3-alkyl, halo-C_1-3-alkyl and oxo.

In an additionally preferred embodiment in combination with any of the above or below embodiments of the first alternative R¹ contains more preferred R¹ contains a carboxylic acid moiety and even more preferred R¹ contains a secondary or tertiary carboxylic acid moiety.

In a preferred embodiment in combination with any of the above or below embodiments of the first alternative NR¹R² is selected from NH₂, NHMe, NHEt, NHⁱPr, NH^tBu, NHCH₂CONH₂, NHCH₂CONMe₂, NHCH₂CH₂OH, NHCH₂CH(CF₃)OH, NHCH₂C(CF₃)₂OH, NHCH₂CH₂OMe, NHCH₂CH₂SO₂Me, NHCH₂CH₂SO₂NH₂, NH(CH₂)₃OH, NH(CH₂)₃OMe, NH(CH₂)₄OH, NH(CH₂)₄OMe, NH(CH₂)₅OH, NH(CH₂)₂CO₂H, NH(CH₂)₃CO₂H, NH(CH₂)₄CO₂H, NH(CH₂)₅CO₂H, NHCH₂CMe₂OH, NHCH(Me)CMe₂OH, NHCH₂CMe₂OMe, NHCH₂CMe₂CO₂H, NHCH₂CMe₂CONH₂, NHCH₂CMe₂CONHMe, NHCH₂CMe₂CONMe₂, NHCH₂CMe₂NHSO₂Me, NH(CH₂)₃SOMe, NH(CH₂)₅SO₂Me, NH(CH₂)₅SO₂NH₂, NH(CH₂)₃NHSO₂Me, NH(CH₂)₂O(CH₂)₂OH, NHCH₂CHMeOH, NH(CH₂)₅SOMe, NH(CH₂)₃SO₂Me,

In a further preferred embodiment in combination with any of the above or below embodiments of the first alternative NR¹R² is selected from NH₂, NHMe, NHEt, NHⁱPr, NH^tBu, NHCH₂CONH₂, NHCH₂CONMe₂, NHCH₂CH₂OH, NHCH₂CH(CF₃)OH, NHCH₂C(CF₃)₂OH, NHCH₂CH₂OMe, NHCH₂CH₂SO₂Me, NHCH₂CH₂SO₂NH₂, NH(CH₂)₃OH, NH(CH₂)₃OMe, NH(CH₂)₄OH, NH(CH₂)₄OMe, NH(CH₂)₅OH, NH(CH₂)₂CO₂H, NH(CH₂)₃CO₂H, NH(CH₂)₄CO₂H, NH(CH₂)₅CO₂H, NHCH₂CMe₂OH, NHCH(Me)CMe₂OH, NHCH₂CMe₂OMe, NHCH₂CMe₂CO₂H, NHCH₂CMe₂CONH₂, NHCH₂CMe₂CONHMe, NHCH₂CMe₂CONMe₂, NHCH₂CMe₂NHSO₂Me, NH(CH₂)₃SOMe, NH(CH₂)₅SO₂Me, NH(CH₂)₃NHSO₂Me, NH(CH₂)₂O(CH₂)₂OH, NHCH₂CHMeOH,

In a more preferred embodiment in combination with any of the above or below embodiments of the first alternative NR¹R² is selected from

In an even more preferred embodiment in combination with any of the above or below embodiments of the first alternative NR¹R² is selected from

In a most preferred embodiment in combination with any of the above or below embodiments of the first alternative NR¹R² is selected from and

In another preferred embodiment in combination with any of the above or below embodiments of the first alternative R³ is selected from wherein

• R³³ is independently selected from H, halogen, CN, C_1-6-alkyl, fluoro-C_1-6-alkyl, C_1-4-alkylene-OH, C_1-4-alkylene-O-C_1-3-alkyl, C_1-4-alkylene-O-fluoro-C_1-3-alkyl, O-C_1-6-alkyl, O-fluoro-C_1-6-alkyl, NH-C_1-6-alkyl, NH-fluoro-C_1-6-alkyl, C_3-10-cycloalkyl, C(O)N(R³⁷)₂,
  wherein alkylene is unsubstituted or substituted with 1 to 3 substituents selected from F, and cycloalkyl is unsubstituted or substituted with 1 to 3 substituents independently selected from F, C_1-3-alkyl and fluoro-C_1-3-alkyl;
• R³⁴ is independently selected from C_1-4-alkylene-OH, C_1-4-alkylene-O-C_1-3-alkyl, C_1-4-alkylene-O-fluoro-C_1-3-alkyl, C_3-10-cycloalkyl, C(O)N(R³⁷)₂, SO₂N(R³⁷)₂,
  wherein alkylene is unsubstituted or substituted with 1 to 3 substituents selected from F, and cycloalkyl is unsubstituted or substituted with 1 to 3 substituents independently selected from F, C_1-3-alkyl and fluoro-C_1-3-alkyl;
• R³⁵ is C_1-6-alkyl or fluoro-C_1-6-alkyl;
• R³⁶ is independently selected from C_1-6-alkyl, fluoro-C_1-6-alkyl, C(O)N(R³⁷)₂ and SO₂N(R³⁷)₂;
• R³⁷ is independently selected from H, C_1-6-alkyl, halo-C_1-6-alkyl, C_0-4-alkylene-C_3-6-cycloalkyl, C_0-4-alkylene-C_3-6-heterocycloalkyl, wherein alkyl and alkylene is unsubtituted or substituted with a substituent selected from halogen, OH, O-C_1-3-alkyl, CN; and cycloalkyl or heterocycloalkyl is unsubstituted or substituted with 1 to 3 substituents independently selected from F, CN, OH, oxo, C_1-3-alkyl and fluoro-C_1-3-alkyl;
• or wherein two R³⁷ when taken together with the nitrogen to which they are attached complete a 3- to 8-membered ring containing carbon atoms and optionally containing 1 or 2 heteroatoms selected from O, S or N, wherein the ring is unsubstituted or substituted with 1 to 4 substitutents independently selected from fluoro, OH, oxo, C_1-4-alkyl and halo-C_1-4-alkyl;
• R³⁸ is independently selected from H, C_1-3-alkyl and fluoro-C_1-3-alkyl;
• R³⁹ is H, F, OH, O-C_1-3-alkyl, O-halo-C_1-3-alkyl;
• W is an annelated C_5-8-cycloalkyl, an annelated 6-membered aryl or an annelated 5- to 6-membered heteroaryl,
  wherein cycloalkyl, aryl and heteroaryl is unsubstituted or substituted with 1 to 2 substituents selected from halogen, methyl and CF₃,
• more preferably, W is an annelated aryl, unsubstituted or substituted with 1 to 2 substituents selected from fluoro, methyl and CF₃;
• X is an annelated saturated heterocycle selected from the group consisting of
• Y is an annelated 5- or 6-membered carbocycle, an annelated 6-membered aryl or an annelated 6-membered heteroaryl containing 1 to 2 nitrogen atoms, wherein the carbocycle, aryl or heteroaryl is unsubstituted or substituted with 1 to 3 substituents selected from fluoro, C_1-3-alkyl and fluoro-C_1-3-alkyl;
• Z is an annelated 6-membered cycle forming a heteroaryl containing 1 to 2 nitrogen atoms, wherein the heteroaryl is unsubstituted or substituted with 1 to 3 substituents selected from fluoro, C_1-3-alkyl and fluoro-C_1-3-alkyl;
• n is independently selected from 1 to 4.

In a more preferred embodiment in combination with any of the above or below embodiments of the first alternative R³ is selected from

• wherein R³³ is selected from C_1-6-alkyl, fluoro-C_1-6-alkyl, C_1-4-alkylene-OH, C_1-4-alkylene-O-C_1-3-alkyl, C_1-4-alkylene-O-fluoro-C_1-3-alkyl, O-C_1-6-alkyl, O-fluoro-C_1-6-alkyl, C_3-10-cycloalkyl, C(O)N(R³⁷)₂, wherein alkylene is unsubstituted or substituted with 1 to 3 substituents selected from F, and cycloalkyl is unsubstituted or substituted with 1 to 3 substituents independently selected from F, C_1-3-alkyl and fluoro-C_1-3-alkyl, more preferably R³³ is selected from fluoro, chloro, CF₃, CHF₂, OCF₃, OCHF₂, methyl, ^tbutyl and CMe₂OH, 1-methylcyclopropyl;
• R³⁴ is selected from C_1-4-alkylene-OH, C_1-4-alkylene-O-C_1-3-alkyl, C_1-4-alkylene-O-fluoro-C_1-3-alkyl, C_3-10-cycloalkyl, C(O)N(R³⁷)₂, S(O₂)N(R³⁷)₂, wherein alkylene is unsubstituted or substituted with 1 to 3 substituents selected from F, and cycloalkyl is unsubstituted or substituted with 1 to 3 substituents independently selected from F, C_1-3-alkyl and fluoro-C_1-3-alkyl;
• R³⁵ is selected from C_1-6-alkyl and fluoro-C_1-6-alkyl;
• R³⁶ is selected from C_1-6-alkyl, fluoro-C_1-6-alkyl, C(O)N(R³⁷)₂, S(O₂)N(R³⁷)₂;
• R³⁷ is indenpedently selected from H, C_1-6-alkyl, halo-C_1-6-alkyl, C_1-6-cycloalkyl, wherein cycloalkyl is unsubstituted or substituted with 1 to 3 substituents independently selected from F, C_1-3-alkyl and fluoro-C_1-3-alkyl,
• or wherein two R³⁷ when taken together with the nitrogen to which they are attached complete a 3- to 8-membered ring containing carbon atoms and optionally containing 1 or 2 heteroatoms selected from O, S or N, wherein the ring is unsubstituted or substituted with 1 to 4 substitutents independently selected from fluoro, oxo, C_1-4-alkyl and halo-C_1-4-alkyl;
• R³⁸ is selected from H, C_1-3-alkyl and fluoro-C_1-3-alkyl;
• R³⁹ is selected from H, F or OH;
• X is an annelated saturated heterocycle selected from the group consisting of and
• Y is an annelated 5- or 6-membered carbocycle, an annelated 6-membered aryl or an annelated 6-membered heteroaryl containing 1 to 2 nitrogen atoms, wherein the carbocycle, aryl or heteroaryl is unsubstituted or substituted with 1 to 3 substituents selected from fluoro, C_1-3-alkyl and fluoro-C_1-3-alkyl;
• Z is an annelated 6-membered cycle forming a heteroaryl containing 1 to 2 nitrogen atoms, wherein the heteroaryl is unsubstituted or substituted with 1 to 3 substituents selected from fluoro, C_1-3-alkyl and fluoro-C_1-3-alkyl; and
• n is selected from 1 to 4.

In an equally more preferred embodiment in combination with any of the above or below embodiments of the first alternative R³ is selected from and wherein

• R³³ is independently selected from H, halogen, C_1-6-alkyl, fluoro-C_1-6-alkyl, C_1-4-alkylene-OH, C_1-4-alkylene-O-C_1-3-alkyl, O-C_1-6-alkyl, O-fluoro-C_1-6-alkyl and C_3-10-cycloalkyl, more preferably R³³ is independently selected from fluoro, chloro, CF₃, CHF₂, OCF₃, OCHF₂, methyl, ^tbutyl and CMe₂OH, 1-methylcyclopropyl;
• one R³⁷ is selected from H, C_1-6-alkyl, halo-C_1-6-alkyl and the other R³⁷ is selected from C_1-6-alkyl, halo-C_1-6-alkyl, C_0-4-alkylene-C_3-6-cycloalkyl, C_0-4-alkylene-C_3-6-heterocycloalkyl, wherein, wherein alkyl and alkylene is unsubtituted or substituted with a substituent selected from halogen, OH, O-C_1-3-alkyl, CN; and cycloalkyl or heterocycloalkyl is unsubstituted or substituted with 1 to 3 substituents independently selected from F, CN, OH, oxo, C_1-3-alkyl and fluoro-C_1-3-alkyl;
• or wherein two R³⁷ when taken together with the nitrogen to which they are attached may complete a 3- to 8-membered ring containing carbon atoms and optionally containing 1 or 2 heteroatoms selected from O, S or N, wherein the ring is unsubstituted or substituted with 1 to 4 substitutents independently selected from fluoro, OH, oxo, C_1-4-alkyl and halo-C_1-4-alkyl;
• W is selected from an annelated C_5-8-cycloakyl, an annelated 6-membered aryl or an annelated 5- to 6-membered heteroaryl,
  wherein cycloalkyl, aryl and heteroaryl is unsubstituted or substituted with 1 to 2 substituents selected from halogen, methyl and CF₃,
• more preferably, W is an annelated aryl, unsubstituted or substituted with 1 to 2 substituents selected from fluoro, methyl and CF_3.

In a more preferred embodiment in combination with any of the above or below embodiments of the first alternative R³ is selected from wherein N(R³⁷)₂ is selected from more preferably N(R³⁷)₂ is selected from and most preferred N(R³⁷)₂ is NH^tBu.

In an equally more preferred embodiment in combination with any of the above or below embodiments of the first alternative R³ is selected from

• wherein R³³ is selected from fluoro, chloro, CHMe₂, CMe₃, cyclopropyl, 1-methylcyclopropyl, CF₃, CHF₂, CMe₂OH, CMe₂OMe, O-CH₂CMe₃, O-CH₂CHMe₃, OCF₃ and OCHF₂;
• R³⁴ is selected from C_1-4-alkylene-OH, C_1-4-alkylene-O-C_1-3-alkyl, C_3-10-cycloalkyl, C(O)N(R³⁷)₂, SO₂N(R³⁷)₂, wherein alkylene is unsubstituted or substituted with 1 to 3 substituents selected from F, and cycloalkyl is unsubstituted or substituted with 1 to 3 substituents independently selected from F, methyl and CF₃; and
• R³⁷ is independently selected from H, C_1-6-alkyl, halo-C_1-6-alkyl.

In an equally more preferred embodiment in combination with any of the above or below embodiments of the first alternative R³ is selected from

In a further preferred embodiment in combination with any of the above or below embodiments of the first alternative R³ is selected from

More preferably, R³ is selected from

Most preferred, R³ is selected from

In a preferred embodiment in combination with any of the above or below embodiments of the first alternative R⁵ is selected from H, C_1-6-alkyl, halo-C_1-6-alkyl or halogen, wherein alkyl is unsubstituted or substituted with 1 to 3 substituents independently selected from the group consisting of O-C_1-6-alkyl, O-halo-C_1-6-alkyl and OH; and R⁶ is selected from H or halogen.

More preferably, R⁵ is selected from H, C_1-3-alkyl, fluoro or chloro, even more preferred R⁵ is selected from H, methyl, fluoro or chloro. Most preferably, R⁵ is methyl.

In a preferred embodiment in combination with any of the above or below embodiments of the first alternative R⁶ is selected from H, fluoro or chloro, more preferably R⁶ is hydrogen.

In a further preferred embodiment in combination with any of the above or below embodiments of the first alternative R⁴ is CR⁸R⁸-R¹⁰; R⁸ is independently selected from H, F, C_1-3-alkyl or halo-C_1-3-alkyl; R¹⁰ is C_3-10-cycloalkyl, wherein cycloalkyl is unsubstituted or substituted with 1 to 6 substituents independently selected from halogen, C_1-6-alkyl, halo-C_1-6-alkyl and cycloalkyl.

In a preferred embodiment in combination with any of the above or below embodiments of the first alternative R⁴ is selected from

In an equally preferred embodiment in combination with any of the above or below embodiments of the first alternative R⁴ is CH₂-(C_4-7-cycloalkyl), wherein C_4-7-cycloalkyl is unsubstituted or substituted with 1 to 4 substituents independently selected from fluoro or methyl.

In a more preferred embodiment in combination with any of the above or below embodiments of the first alternative R⁴ is and

Even more preferred, R⁴ is and most preferred, R⁴ is CH₂-cyclohexyl.

In another preferred embodiment in combination with any of the above or below embodiments of the first alternative the compound of Formula (1) is selected from the group consisting of and an enantiomer, diastereomer, tautomer, N-oxide, solvate and pharmaceutically acceptable salt thereof.

In a more preferred embodiment in combination with any of the above or below embodiments of the first alternative the compound of Formula (1) is selected from the group consisting of and an enantiomer, diastereomer, tautomer, solvate and pharmaceutically acceptable salt thereof.

In a second alternative, the present invention provides a compound of Formula (1) an enantiomer, diastereomer, tautomer, N-oxide, solvate, formulation and pharmaceutically acceptable salt thereof,
wherein

• R¹ is selected from
• a 4-membered heterocycloalkyl group containing one heteroatom selected from the group consisting of N, O and S, or
• C_1-10-alkyl substituted with a group selected from halogen, CN, OR¹¹, SO_yR¹¹, SO₃H, NR¹¹SO₂R¹¹, SO₂NR¹¹R¹², CO₂R¹¹, COR¹¹, CONR¹¹R¹², NR¹¹-CO-R¹¹, NR¹¹-CO-NR¹¹R¹², NR¹¹-SO₂-NR¹¹R¹², NR¹¹R¹² and a 4-membered heterocycloalkyl group containing one heteroatom selected from the group consisting of N, O and S, or
• C_0-1-alkylene-C_3-10-cycloalkyl substituted with a group selected from halogen, CN, SO_yR¹¹, NR¹¹SO₂R¹¹, SO₂NR¹¹R¹², CO₂R¹¹, CONR¹¹R¹², NR¹¹-CO-R¹¹, NR¹¹-CO-NR¹¹R¹², NR¹¹-SO₂-NR¹¹R¹² and NR¹¹R¹², or
• C_2-10-alkylene-C_3-10-cycloalkyl, C_2-10-alkylene-O-C_3-10-cycloalkyl, C_2-10-alkylene-C_5-10-heterocycloalkyl and C_2-10-alkylene-O-C_5-10-heterocycloalkyl,
• wherein alkyl, alkylene, cycloalkyl and heterocycloalkyl are optionally substituted with 1 to 7 substituents independently selected from the group consisting of OH, oxo, CN, O-C_1-6-alkyl, O-halo-C_1-6-alkyl, C_1-6-alkyl, halo-C_1-6-alkyl, halogen, CO₂R¹¹, CONR¹¹R¹², SO₂R¹¹, SO₂NR¹¹R¹², NR¹¹COR¹¹, NR¹¹SO₂R¹¹, C_3-6-cycloalkyl, O-C_3-6-cycloalkyl, C_3-6-heterocycloalkyl, O-C_3-6-heterocycloalkyl, O-C_2-6-alkylene-OR¹¹ and NR¹¹R¹²;
• R² is selected from the group consisting of H, C_1-6-alkyl, halo-C_1-6-alkyl and hydroxy-C_1-6-alkyl;
• or R¹ and R² when taken together with the nitrogen to which they are attached complete a 3-to 8-membered ring containing carbon atoms and optionally containing 1 or 2 heteroatoms selected from O, S or N, wherein the ring is unsubstituted or substituted with 1 to 4 substitutents independently selected from halogen, oxo, CN, OR¹¹, SO_yR¹¹, SO₃H, NR¹¹SO₂R¹¹, SO₂NR¹¹R¹², C_0-6-alkylene-CO₂R¹¹, CONR¹¹R¹², COR¹¹, NR¹¹-CO-R¹¹, NR¹¹-CO-NR¹¹R¹², NR¹¹-SO₂-NR¹¹R¹², NR¹¹R¹², C_1-6-alkyl, halo-C_1-6-alkyl, hydroxy-C_1-6-alkyl, C_3-6-cycloalkyl, O-C_3-6-cycloalkyl, C_3-6-heterocycloalkyl and O-C_3-6-heterocycloalkyl,
  wherein cycloalkyl and heterocycloalkyl are unsubstituted or substituted with 1 to 4 substitutents independently selected from halogen, C_1-3-alkyl, halo-C_1-3-alkyl and oxo;
• R³ is a 6- or 10-membered mono- or bicyclic aryl or a 6- to 10-membered mono- or bicyclic heteroaryl containing 1 or 2 heteroatom selected from the group consisting of N, O and S,
• wherein aryl and heteroaryl are unsubstituted or substituted with 1 to 5 substituents independently selected from halogen, CN, C_1-6-alkyl, C_3-10-cycloalkyl, C_0-6-alkylene-C_3-10-heterocycloalkyl, C_0-6-alkylene-O-R³¹, C_0-6-alkylene-COOR³¹, C_0-6-alkylene-C(O)R³¹, C_0-6-alkylene-C(O)N(R³¹)₂, C_0-6-alkylene-N(R³¹)C(O)R³¹, C_0-6-alkylene-SO₂-N(R³¹)₂, C_0-6-alkylene-N(R³¹)SO₂-R³¹, C_0-6-alkylene-SO₂-R³¹, C_0-6-alkylene-SO-R³¹ and C_0-6-alkylene-N(R³¹)₂,
  wherein alkyl, alkylene, cycloalkyl and heterocycloalkyl are unsubstituted or substituted by 1 to 4 substituents independently selected from the group consisting of halogen, CN, C_1-3-alkyl, halo-C_1-3-alkyl, C_3-6-cycloalkyl, C_3-6-heterocycloalkyl, OH, O-C_1-3-alkyl, O-halo-C_1-3-alkyl, O-C_3-6-cycloalkyl, O-C_3-6-heterocycloalkyl, oxo, N(R³²)₂, COOH, CON(R³²)₂, CN and NR³²-COR³²,
• and wherein optionally two adjacent substituents complete a 3- to 8-membered saturated or partially unsaturated ring containing carbon atoms and optionally containing 1 to 3 heteroatoms selected from O, S or N, wherein the ring is unsubstituted or substituted with 1 to 6 substituents independently selected from halogen, C_1-6-alkyl, halo-C_1-6-alkyl, C_3-6-cycloalkyl, C_3-6-heterocycloalkyl, oxo, OH, O-C_1-6-alkyl and O-halo-C_1-6-alkyl;
• R⁴ is SO₂-(CR⁸R⁸)_yR⁷, SO₂-NR¹²R⁷, (CR⁸R⁸)_x-R¹⁰ or C_3-6-cycloalkyl, which is spirocyclic fused with C_3-10-cycloalkyl;
• R⁵ is selected from H, C_1-6-alkyl, halo-C_1-6-alkyl, CHO, CON(R⁵²)₂ or halogen, wherein alkyl is unsubstituted or substituted with 1 to 3 substituents independently selected from the group consisting of O-C_1-6-alkyl, O-halo-C_1-6-alkyl and OH;
• R⁶ is selected from H, C_1-6-alkyl, halo-C_1-6-alkyl or halogen;
• R⁷ is selected from C_3-10-cycloalkyl and C_3-10-heterocycloalkyl,
  wherein cycloalkyl and heterocycloalkyl are unsubstituted or substituted with 1 to 3 substituents independently selected from the group consisting of halogen, OH, oxo, O-C_1-6-alkyl, O-halo-C_1-6-alkyl, C_1-6-alkyl, halo-C_1-6-alkyl, cycloalkyl and heterocycloalkyl;
• R⁸ is independently selected from H, F, C_1-3-alkyl, halo-C_1-3-alkyl or OH;
• R¹⁰ is C_3-10-cycloalkyl, wherein cycloalkyl is unsubstituted or substituted with 1 to 6 substituents independently selected from halogen, OH, oxo, O-C_1-6-alkyl, O-halo-C_1-6-alkyl, C_1-6-alkyl, halo-C_1-6-alkyl, cycloalkyl, heterocycloalkyl, and optionally two adjacent substituents together complete a 6-membered aryl ring wherein the ring is unsubstituted or substituted with 1 to 3 substituents independently selected from halogen, C_1-2-alkyl, halo-C_1-2-alkyl;
• R¹¹ is independently selected from H, C_1-6-alkyl, C_0-6-alkylene-C_3-6-cycloalkyl, C_0-6-alkylene-C_3-6-heterocycloalkyl, wherein alkyl, alkylene, cyclolalkyl and heterocycloalkyl are unsubstituted or substituted with 1 to 6 substituents independently selected from halogen, OH, oxo, C_1-3-alkyl, halo-C_1-3-alkyl, O-C_1-3-alkyl, O-halo-C_1-3-alkyl and SO₂-C_1-3-alkyl;
• R¹² is independently selected from H, C_1-6-alkyl and halo-C_1-6-alkyl;
• R³¹ is independently selected from H, C_1-6-alkyl, halo-C_1-6-alkyl, C_0-6-alkylene-C_3-6-cycloalkyl, C_0-6-alkylene-C_3-6-heterocycloalkyl, 5- or 6-membered heteroaryl and 6-membered aryl, wherein alkyl, alkylene, cyclolalkyl, heterocycloalkyl, aryl and heteroaryl are unsubstituted or substituted with 1 to 6 substituents independently selected from halogen, CN, OH, oxo, C_1-3-alkyl, halo-C_1-3-alkyl, O-C_1-3-alkyl, O-halo-C_1-3-alkyl and SO₂-C_1-3-alkyl;
• and optionally wherein two R³¹ when taken together with the nitrogen to which they are attached complete a 3- to 8-membered ring containing carbon atoms and optionally containing 1 or 2 heteroatoms selected from O, S or N, wherein the ring is unsubstituted or substituted with 1 to 4 substitutents independently selected from fluoro, OH, oxo, C_1-4-alkyl and halo-C_1-4-alkyl;
• R³² is independently selected from H, C_1-6-alkyl and halo-C_1-6-alkyl;
• R⁵² is independently selected from H, C_1-3-alkyl and halo-C_1-3-alkyl;
• x is independently selected from 1 and 2;
• y is independently selected from 0, 1 and 2.

In a further preferred embodiment in combination with any one of the above or below embodiments of the second alternative NR¹R² is selected from NHCH₂CONH₂, NHCH₂CONMe₂, NHCH₂CH₂OH, NHCH₂C(CF₃)₂OH, NHCH₂CH₂OMe, NHCH₂CH₂SO₂Me, NHCH₂CH₂SO₂NH₂, NH(CH₂)₃OH, NH(CH₂)₃OMe, NH(CH₂)₄OH, NH(CH₂)₄OMe, NH(CH₂)₅OH, NH(CH₂)₂CO₂H, NH(CH₂)₃CO₂H, NH(CH₂)₄CO₂H, NH(CH₂)₅CO₂H, NHCH₂CMe₂OH, NHCH(Me)CMe₂OH, NHCH₂CMe₂OMe, NHCH₂CMe₂CO₂H, NHCH₂CMe₂CONH₂, NHCH₂CMe₂CONHMe, NHCH₂CMe₂CONMe₂, NHCH₂CMe₂NHSO₂Me, NH(CH₂)₃SOMe, NH(CH₂)₅SO₂Me, NH(CH₂)₅SO₂NH₂, NH(CH₂)₃NHSO₂Me, NH(CH₂)₂O(CH₂)₂OH, NHCH₂CHMeOH, NH(CH₂)₅SOMe, NH(CH₂)₃SO₂Me,

In a more preferred embodiment in combination with any one of the above or below embodiments of the second alternative NR¹R² is selected from NHCH₂CONH₂, NHCH₂CONMe₂, NHCH₂CH₂OH, NHCH₂C(CF₃)₂OH, NHCH₂CH₂OMe, NHCH₂CH₂SO₂Me, NHCH₂CH₂SO₂NH₂, NH(CH₂)₃OH, NH(CH₂)₃OMe, NH(CH₂)₄OH, NH(CH₂)₄OMe, NH(CH₂)₅OH, NH(CH₂)₂CO₂H, NH(CH₂)₃CO₂H, NH(CH₂)₄CO₂H, NH(CH₂)₅CO₂H, NHCH₂CMe₂OH, NHCH(Me)CMe₂OH, NHCH₂CMe₂OMe, NHCH₂CMe₂CO₂H, NHCH₂CMe₂CONH₂, NHCH₂CMe₂CONHMe, NHCH₂CMe₂CONMe₂, NHCH₂CMe₂NHSO₂Me, NH(CH₂)₃SOMe, NH(CH₂)₅SO₂Me, NH(CH₂)₃NHSO₂Me, NH(CH₂)₂O(CH₂)₂OH, NHCH₂CHMeOH,

More preferably, NR¹R² is selected from and most preferred NR¹R² is

In another preferred embodiment in combination with any one of the above or below embodiments of the second alternative R³ is wherein

• R³³ is independently selected from C_1-6-alkyl and fluoro-C_1-6-alkyl;
• R³⁴ is independently selected from halogen, C_1-6-alkyl, fluoro-C_1-6-alkyl, O-C_1-6-alkyl, O-fluoro-C_1-6-alkyl, NH-C_1-6-alkyl and NH-fluoro-C_1-6-alkyl;
• R³⁹ is selected from H, F and OH.

In yet another preferred embodiment in combination with any one of the above or below embodiments of the second alternative R³ is selected from More preferably, R³ is Even more preferably, R³ is

In a further preferred embodiment in combination with any one of the above or below embodiments of the second alternative R⁵ is selected from H, C_1-6-alkyl, halo-C_1-6-alkyl or halogen, wherein alkyl is unsubstituted or substituted with 1 to 3 substituents independently selected from the group consisting of O-C_1-6-alkyl, O-halo-C_1-6-alkyl and OH.

More preferably, R⁵ is selected from H, C_1-3-alkyl, fluoro or chloro, even more preferred R⁵ is selected from H, methyl, fluoro or chloro. Most preferably, R⁵ is methyl.

In a preferred embodiment in combination with any of the above or below embodiments of the second alternative R⁶ is selected from H, fluoro or chloro, more preferably R⁶ is hydrogen.

In another preferred embodiment in combination with any one of the above or below embodiments of the second alternative R⁴ is SO₂-R⁷, SO₂-NR¹²R⁷, CHR⁸-R¹⁰ and (CH)₂R¹⁰;

• R⁷ is independently selected from C_3-10-cycloalkyl and C_3-10-heterocycloalkyl,
  wherein cycloalkyl and heterocycloalkyl are unsubstituted or substituted with 1 to 3 substituents independently selected from the group consisting of fluoro, OH, C_1-6-alkyl, halo-C_1-6-alkyl and cycloalkyl;
• R⁸ is H, F, C_1-3-alkyl or halo-C_1-3-alkyl;
• R¹⁰ is C_3-10-cycloalkyl, wherein cycloalkyl is unsubstituted or substituted with 1 to 6 substituents independently selected from halogen, C_1-6-alkyl, halo-C_1-6-alkyl and cycloalkyl.

In a further preferred embodiment in combination with any one of the above or below embodiments of the second alternative R⁴ is selected from More preferably, R⁴ is CH₂-C_4-7-cycloalkyl, most preferably, R⁴ is CH₂-cyclohexyl.

In yet another preferred embodiment in combination with any of the above or below embodiments of the second alternative, the compound of Formula (1) is selected from the group consisting of and an enantiomer, diastereomer, tautomer, N-oxide, solvate and pharmaceutically acceptable salt thereof.

More preferred are compounds of Formula (1) selected from the group consisting of

The invention also provides the compound of the invention for use as a medicament.

Also provided is the compound of the invention for use in treating RORy mediated inflammatory and autoimmune diseases.

Preferably, the disease is selected from the group consisting of rheumatoid arthritis, ankylosing spondylitis, lupus erythematosus, psoriasis, psoriatic arthritis, atopic eczema, inflammatory bowel diseases such as Crohn's disease, asthma, mucosal leishmaniasis, multiple sclerosis, systemic sclerosis, type 1 diabetes, Kawasaki disease, Hashimoto's thyroiditis, chronic graft-versus-host disease, acute graft-versus-host disease, Celiac Sprue, idiopathic thrombocytopenic thromobotic purpura, myasthenia gravis, Sjorgren's syndrome, scleroderma, ulcerative colitis, epidermal hyperplasia, glomerulonephritis, chronic obstructive pulmonary disease and amyotrophic lateral sclerosis. More preferably, the disease is selected from the group consisting of rheumatoid arthritis, ankylosing spondylitis, lupus erythematosus, psoriasis, psoriatic arthritis, atopic eczema, inflammatory bowel diseases such as Crohn's disease, asthma, multiple sclerosis, type 1 diabetes, chronic obstructive pulmonary disease and amyotrophic lateral sclerosis. Most preferred, the disease is rheumatoid arthritis or psoriasis.

Also provided is a pharmaceutical composition comprising the compound of the invention and a pharmaceutically acceptable carrier.

In the context of the present invention C_1-12-alkyl means a saturated hydrocarbon chain having 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 carbon atoms, which may be straight chained or branched. Examples thereof include methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, neopentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl and dodecyl.

The term "halo-C_1-12-alkyl" means that one or more hydrogen atoms in the alkyl chain are replaced by a halogen. A subset of this term is "fluoro-C_1-4-alkyl", wherein one or more hydrogen atoms in the alkyl chain are replaced by a fluorine atom. Preferred examples thereof are CF₃, CH₂CF₃ and CH₂CH₂F.

C_2-12-alkenyl means a hydrocarbon chain having 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 carbon atoms, which may be straight chained or branched, containing at least one carbon to carbon double bond. Examples thereof include ethenyl, propenyl, dodecenyl, 2-methylenehexyl and (2E,4E)-hexa-2,4-dienyl.

C_2-12-alkynyl means a hydrocarbon chain having 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 carbon atoms, which may be straight chained or branched, containing at least one carbon to carbon triple bond. Examples thereof include ethynyl, propynyl and dodecynyl.

A "C_0-6-alkylene" means that the respective group is divalent and connects the attached residue with the remaining part of the molecule. Moreover, in the context of the present invention, "C₀-alkylene" is meant to represent a bond.

A C_3-10-cycloalkyl group means a saturated mono-, bi- or multicyclic ring system comprising 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms. Examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, bicyclo[2.2.2]octyl, bicyclo[2.2.1]heptyl, pentacyclo[4.2.0.0^2,5.0^3,8.0^4,7]octyl and adamantyl.

A C_3-10-heterocycloalkyl group means a saturated or partially unsaturated 3, 4, 5, 6, 7, 8, 9 or 10-membered carbon mono-, bi- or multicyclic ring wherein 1, 2 or 3 carbon atoms are replaced by 1, 2 or 3 heteroatoms, respectively, wherein the heteroatoms are independently selected from N, O and S. Examples thereof include epoxidyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, tetrahydropyranyl, 1,4-dioxanyl, morpholinyl, 4-quinuclidinyl, 1,4-dihydropyridinyl and 3,6-dihydro-2H-thiopyranyl. The C_3-10-heterocycloalkyl group can be connected via a carbon or nitrogen atom, if not stated otherwise.

A 5- to 10-membered mono- or bicyclic heteroaryl system containing up to 4 heteroatoms means a monocyclic heteroaromatic ring such as pyrrolyl, imidazolyl, furanyl, thiophenyl, pyridinyl, pyrimidinyl, pyrazinyl, pyrazolyl, oxazolyl, isoxazolyl, triazolyl, oxadiazolyl and thiadiazolyl. It further means a bicyclic ring system wherein the heteroatom(s) may be present in one or both rings including the bridgehead atoms. Examples thereof include quinolinyl, isoquinolinyl, quinoxalinyl, benzimidazolyl, benzisoxazolyl, benzodioxanyl, benzofuranyl, benzoxazolyl, indolyl, indolizinyl and pyrazolo[1,5-a]pyrimidinyl. The nitrogen or sulphur atom of the heteroaryl system may also be optionally oxidized to the corresponding N-oxide, S-oxide or S,S-dioxide. If not stated otherwise, the heteroaryl system can be connected via a carbon or nitrogen atom. Examples for N-linked heterocycles are

A 6- to 10-membered mono- or bicyclic aryl system means an aromatic carbon cycle such as phenyl or naphthalenyl.

The term "N-oxide" denotes compounds, there the nitrogen in the heteroaromatic system (preferably pyridinyl) is oxidized. Such compounds can be obtained in a known manner by reacting a compound of the present invention (such as in a pyridinyl group) with H₂O₂ or a peracid in an inert solvent.

Halogen is selected from fluorine, chlorine, bromine and iodine. The preferred halogen is fluorine.

Furthermore, the compounds of the present invention are partly subject to tautomerism. For example, if a heteroaromatic group containing a nitrogen atom in the ring is substituted with a hydroxy group on the carbon atom adjacent to the nitrogen atom, the following tautomerism can appear:

When a substitution of a residue with cycloalkyl or heterocycloalkyl is described, it is understood that the substitution can be connected straight and, when the connecting carbon atom is sp³-hybridized, in addition spirocyclic. For example, when cyclohexan is substitued with the heterocycloalkyl group oxetan-3-yl, the following structures are possible:

It will be appreciated by the skilled person that when lists of alternative substituents include members which, because of their valency requirements or other reasons, cannot be used to substitute a particular group, the list is intended to be read with the knowledge of the skilled person to include only those members of the list which are suitable for substituting the particular group.

The compounds used in the present invention can be in the form of a pharmaceutically acceptable salt or a solvate. The term "pharmaceutically acceptable salts" refers to salts prepared from pharmaceutically acceptable non-toxic bases or acids, including inorganic bases or acids and organic bases or acids. In case the compounds of the present invention contain one or more acidic or basic groups, the invention also comprises their corresponding pharmaceutically or toxicologically acceptable salts, in particular their pharmaceutically utilizable salts. Thus, the compounds of the present invention which contain acidic groups can be used according to the invention, for example, as alkali metal salts, alkaline earth metal salts or ammonium salts. More precise examples of such salts include sodium salts, potassium salts, calcium salts, magnesium salts or salts with ammonia or organic amines such as, for example, ethylamine, ethanolamine, triethanolamine or amino acids. The compounds of the present invention which contain one or more basic groups, i.e. groups which can be protonated, can be used according to the invention in the form of their addition salts with inorganic or organic acids. Examples of suitable acids include hydrogen chloride, hydrogen bromide, phosphoric acid, sulfuric acid, nitric acid, methanesulfonic acid, p-toluenesulfonic acid, naphthalenedisulfonic acids, oxalic acid, acetic acid, tartaric acid, lactic acid, salicylic acid, benzoic acid, formic acid, propionic acid, pivalic acid, diethylacetic acid, malonic acid, succinic acid, pimelic acid, fumaric acid, maleic acid, malic acid, sulfaminic acid, phenylpropionic acid, gluconic acid, ascorbic acid, isonicotinic acid, citric acid, adipic acid and other acids known to the person skilled in the art. If the compounds of the present invention simultaneously contain acidic and basic groups in the molecule, the invention also includes, in addition to the salt forms mentioned, inner salts or betaines (zwitterions). The respective salts can be obtained by customary methods which are known to the person skilled in the art like, for example, by contacting these with an organic or inorganic acid or base in a solvent or dispersant, or by anion exchange or cation exchange with other salts. The present invention also includes all salts of the compounds of the present invention which, owing to low physiological compatibility, are not directly suitable for use in pharmaceuticals but which can be used, for example, as intermediates for chemical reactions or for the preparation of pharmaceutically acceptable salts.

In practical use, the compounds used in the present invention can be combined as the active ingredient in intimate admixture with a pharmaceutical carrier according to conventional pharmaceutical compounding techniques. The carrier may take a wide variety of forms depending on the form of preparation desired for administration, e.g., oral or parenteral (including intravenous). In preparing the compositions for oral dosage form, any of the usual pharmaceutical media may be employed, such as, for example, water, glycols, oils, alcohols, flavoring agents, preservatives, coloring agents and the like in the case of oral liquid preparations, such as, for example, suspensions, elixirs and solutions; or carriers such as starches, sugars, microcrystalline cellulose, diluents, granulating agents, lubricants, binders, disintegrating agents and the like in the case of oral solid preparations such as, for example, powders, hard and soft capsules and tablets, with the solid oral preparations being preferred over the liquid preparations.

Because of their ease of administration, tablets and capsules represent the most advantageous oral dosage unit form in which case solid pharmaceutical carriers are obviously employed. If desired, tablets may be coated by standard aqueous or non-aqueous techniques. Such compositions and preparations should contain at least 0.1 percent of active compound. The percentage of active compound in these compositions may, of course, be varied and may conveniently be between about 2 percent to about 60 percent of the weight of the unit. The amount of active compound in such therapeutically useful compositions is such that an effective dosage will be obtained. The active compounds can also be administered intranasally as, for example, liquid drops or spray.

The tablets, pills, capsules and the like may also contain a binder such as gum tragacanth, acacia, corn starch or gelatin; excipients such as dicalcium phosphate; a disintegrating agent such as corn starch, potato starch, alginic acid; a lubricant such as magnesium stearate; and a sweetening agent such as sucrose, lactose or saccharin. When a dosage unit form is a capsule, it may contain, in addition to materials of the above type, a liquid carrier such as a fatty oil.

Various other materials may be present as coatings or to modify the physical form of the dosage unit. For instance, tablets may be coated with shellac, sugar or both. A syrup or elixir may contain, in addition to the active ingredient, sucrose as a sweetening agent, methyl and propylparabens as preservatives, a dye and a flavoring such as cherry or orange flavor.

The compounds used in the present invention may also be administered parenterally. Solutions or suspensions of these active compounds can be prepared in water suitably mixed with a surfactant such as hydroxy-propylcellulose. Dispersions can also be prepared in glycerol, liquid polyethylene glycols and mixtures thereof in oils. Under ordinary conditions of storage and use, these preparations contain a preservative to prevent the growth of microorganisms.

The pharmaceutical forms suitable for injectable use include sterile aqueous solutions or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions. In all cases, the form must be sterile and must be fluid to the extent that easy syringability exists. It must be stable under the conditions of manufacture and storage and must be preserved against the contaminating action of microorganisms such as bacteria and fungi. The carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (e.g., glycerol, propylene glycol and liquid polyethylene glycol), suitable mixtures thereof, and vegetable oils.

Any suitable route of administration may be employed for providing a mammal, especially a human, with an effective dose of a compound of the present invention. For example, oral, rectal, topical, parenteral (including intravenous), ocular, pulmonary, nasal and the like may be employed. Dosage forms include tablets, troches, dispersions, suspensions, solutions, capsules, creams, ointments, aerosols and the like. Preferably compounds of the present invention are administered orally.

The effective dosage of active ingredient employed may vary depending on the particular compound employed, the mode of administration, the condition being treated and the severity of the condition being treated. Such dosage may be ascertained readily by a person skilled in the art.

When treating or preventing RORγ-mediated conditions for which compounds of Formula (1) are indicated, generally satisfactory results are obtained when the compounds are administered at a daily dosage of from about 0.1 milligram to about 100 milligram per kilogram of mammal body weight, preferably given as a single daily dose or in divided doses two to six times a day, or in sustained release form. For most large mammals, the total daily dosage is from about 1.0 milligram to about 1000 milligrams, preferably from about 1 milligram to about 50 milligrams. In the case of a 70 kg adult human, the total daily dose will generally be from about 7 milligrams to about 350 milligrams. This dosage regimen may be adjusted to provide the optimal therapeutic response.

The present invention describes modulators, in the following also referred to as ligands, which bind to the RORy receptor. Surprisingly, it has been found that compounds of Formula (1) act as modulators of the RORγ receptor.

The RORγ receptor is considered to be involved in thymocyte development, thus the modulators described herein may be useful in the treatment of inflammatory skin diseases such as atopic eczema and psoriasis. It is further suggested that down-modulation of RORγ transcriptional activity with a ligand could result in a shift of the immune response towards a Th2 type response which could be beneficial in the treatment of certain allergic inflammatory conditions such as rheumatoid arthritis, systemic lupus erythomatosis, inflammatory bowel disease (Crohn's Disease) and multiple sclerosis (Tesmer et. al., Immunol. Rev. 2008, 223:97).

The compounds of Formula (1) show antagonistic activity, with respect to the dose dependent modulation of the constitutive interaction of the RORγ ligand binding domain with peptides derived from the co-activators such as SRC-1, TRAP 220 or TIF-2.

It has been surprisingly found that the interaction between RORγ ligand binding domain and the peptides can be determined by a homogenous FRET based ligand-sensing assays. Even more surprising was the identification of compounds of Formula (1) as ligands for RORγ.

The identification of high affinity ligands for RORγ with agonistic and antagonistic properties is the basis to enable experts knowledgeable in the field to establish assays for the identification of novel agonistic and antagonistic RORγ ligands from libraries of small molecules. The identification of ligands which bind to and modulate the activity of RORγ1 and RORγt is the first mandatory step to develop new small molecule based medicines with a potential to be developed for the treatment of diseases which are directly or indirectly controlled by the activity of RORγ1 or RORγt. Such diseases include but are not restricted to inflammatory diseases, asthma, rheumatoid arthritis, autoimmune diseases or diseases with an autoimmune component such as systemic lupus erythomatosis, inflammatory bowel disease (Crohn's disease), ulcerative colitis, inflammatory skin diseases such as atopic eczema or psoriasis, multiple sclerosis or similar diseases.

The compounds of the present invention can be prepared by a combination of methods known in the art including the procedures described in Schemes I to III below. Pyrrole-3-esters of general structure A (Scheme I) can be N-derivatized by alkylation with alkyl halides, by reaction with sulfonyl chlorides or sulfamoyl chlorides in the presence of appropriate bases in appropriate solvents. The introduction of an aromatic or heteroaromatic substituents in the 5-position of intermediates B (Scheme I) can be achieved either by bromination with N-bromosuccinimide (NBS) and subsequent Suzuki cross coupling with boronic esters or boronic acids or by an Ir-catalyzed direct borylation (as described in J. Am. Chem. Soc. 2007, 129:15434) of intermediate B (Scheme I), followed by boronic ester hydrolysis and Suzuki cross coupling with halo-aromatics or halo-heteroaromatics. The order of alkylation and bromination to prepare intermediates C can be inverted as depicted in Scheme I. The common intermediate E (Scheme I) can be further transformed into carboxamides by ester hydrolysis and amide formation using methods known to those skilled in the art.

Alternatively, for purposes of tailored late stage derivatization, the formation of the amide can be performed first, followed by bromination and Suzuki cross-coupling as final step, as depicted in Scheme II.

In alternative to Pd-catalyzed cross coupling reactions the 2-position of pyrrole A (Scheme III) can be acylated and the resulting ketone intermediate B (Scheme III) can be further transformed into heteroaromatics containing analogues of the general formula C in Scheme III, using methods described in Org. Lett. 2008, 10:2897. Again, intermediate C (Scheme III) can be further transformed into carboxamides by ester hydrolysis and amide formation using methods known to those skilled in the art.

Ac

acetyl

ACN

acetonitrile

aq.

aqueous

B₂Pin₂

4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi-1,3,2-dioxaborolane

CC

flash chromatography on silica gel

COD

cyclooctadiene

Cy

cyclohexyl

dba

dibenzylideneacetone

DCE

1,2-dichlroroethane

DCM

dichloromethane

DIPEA

diisopropylethylamine

DMAP

4-Dimethylaminopyridine

DMF

N,N-dimethylformamide

dppf

1,1'-bis(diphenylphosphino)ferrocene

dppp

1,3-bis(diphenylphosphino)propane

dtbpy

4,4'-di-tert-butyl-2,2'-bipyridine

EA

ethyl acetate

HATU

O-(7-azabenzotriazole-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate

MOM

methoxymethyl

MTBE

tert-butylmethylether

NBS

N-bromosuccinimide

NCS

N-chlorosuccinimide

Pin

pinacolato (OCMe₂CMe₂O)

PE

petroleum ether

prep.

preparative

rt

room temperature

TBAB

tertabutylammonium bromide

Tf

trifluoromethanesulfonyl

TEA

triethylamine

TFA

trifluoroacetic acid

THF

tetrahydrofuran

TLC

thin layer chromatography

The synthesis of the following Preparative Examples is described in WO2012/139775:

To a solution of 2-(tert-butyl)phenol (30.0 g, 200 mmol) in CHCl₃ (600 mL) was added tetra-n-butyl ammonium tribromide (121 g, 250 mmol) and the solution was stirred for 2 h at rt, concentrated and the crude product was partitioned between Et₂O and water. The organic layer was washed sequentially with 1M HCl twice and brine twice. The organic layer was separated and dried over MgSO₄, concentrated and purified by CC (PE/EA = 7/1) to give compound P7a (39.9 g, 89%) as a colorless solid.

NaH (4.40 g, 110 mmol) and MOMCI (9.60 g, 120 mmol) were gradually added to a solution of compound P7a (22.8 g, 100 mol) in dry DMF (300 mL) while cooling on ice and the mixture was stirred at 0°C overnight, poured into ice water and extracted with EA (3x). The combined organic layer was washed with water (3x) and brine consecutively, dried over Na₂SO₄, concentrated and purified by CC (PE/EA = 100/1) to give compound P7b (24.9 g, 92%) as a light yellow oil.

A solution of compound P7b (24.2 g, 89.0 mmol), B₂Pin₂ (24.1 g, 95.0 mmol), KOAc (9.31 g, 95.0 mmol) and Pd(dppf)Cl₂ (4.00 g) in dry DMF (500 mL) was heated at 90°C overnight under N₂, concentrated and the residue was partitioned between water and EA. The aq. layer was extracted with EA and the combined organic layers were washed with water twice and brine consecutively. The organic layer was dried over Na₂SO₄, filtered, concentrated and purified by CC (PE/EA = 5/1) to give compound P7 (15.4 g, 54%) as a colorless solid.

A mixture of 6-tert-butyl-4-hydroxy-2H-pyran-2-one (38 g, 168 mmol) and aq. NH₄OH (150 mL, 30%) in dry toluene (200 mL) was heated at reflux for 1 h, concentrated and purified by CC (PE/EA = 5/1) to give compound P8a (22.5 g, 80%) as a colorless solid.

To a solution of compound P8a (9.7 g, 60 mmol) in DMF (100 mL) was added POBr₃ (17.2 g, 60 mmol) and the mixture was heated at 90°C for 2 h, was concentrated, diluted with water and extracted with EA. The organic layer was washed with brine (3x), concentrated and purified by CC (PE/EA = 5/1) to give compound P8b (22.5 g, 80%) as a yellow solid.

To a solution of compound P8b (2.0 g, 8.66 mmol) in dry DMF (20 mL) was added NaH (0.62 g, 26.0 mmol) under N₂ and the mixture was stirred at rt for 1 h. Then 1-bromo-2,2-dimethylpropane (2.37 g, 15.7 mmol) was added and the resulting mixture was heated at 80°C overnight, quenched with water (10 mL) and extracted with EA twice. The combined organic layers were washed with brine (3x), concentrated and purified by CC (PE/EA = 50/1) to give compound P8c (0.5 g, 20%) as an oil.

A mixture of compound P8c (2.2 g, 7.72 mmol), B₂Pin₂ (2.94 g, 11.6 mmol), KOAc (1.13 g, 11.6 mmol) and Pd(dppf)Cl₂ (200 mg) in dry DMF (20 mL) was heated at 90°C under N₂ overnight, quenched with water and extracted with EA twice. The combined organic layers were washed with brine (3x), concentrated and purified by CC (PE/EA = 50/1) to give compound P8 (2.5 g, 97%) as an oil.

Under N₂ a catalyst stock solution was prepared by weighing [(COD)Ir(µ-OMe)]₂ (104 mg, 0.312 mmol Ir), dtbpy (84 mg, 0.312 mmol) and B₂Pin₂ (2.64 g, 10.4 mmol) into a vial followed by the volumetric addition of degassed MTBE to make up a 25 mL solution which upon shaking developed a deep red color. The solution was transferred to a vial and sealed with a rubber septum. Under N₂, a vial was charged with 2,6-di-tert-butylpyridine (1.91 g, 10.0 mmol) followed by 25 mL of the catalyst stock solution. The reaction was heated at 80°C for 2 h, concentrated and purified by CC (PE/EA = 8/1) to give compound P9 (1.89 g, 60%) as a colorless solid.

To a solution of 1-(cyclohexylmethyl)-2-ethyl-1H-pyrrole-3-carboxylate (prepared according to Example 1d, 2.12 g, 8.51 mmol) in THF (20 mL) was added [(COD)Ir(µ-OMe)]₂ (167 mg, 0.25 mmol), dtbpy (137 mg, 0.51 mmol) and B₂Pin₂ (2.38 g, 9.37 mmol) and the solution was stirred overnight at 100°C under N₂, concentrated and purified by CC (PE/EA = 50/1) to give compound P18a (2.24 g, 70%) as a colorless solid.

To a solution of P18a (1.50 g, 4.00 mmol) in a mixture of acetone (15 mL) and water (15 mL) was added sodium periodate (2.55 g, 12.0 mmol) and ammonium acetate (1.00 g, 13 mmol) at rt and the solution was stirred at reflux for 2 d, concentrated and extracted with EA. The organic layer was washed with 0.1M HCl and brine consecutively, dried over Na₂SO₄, filtered and concentrated to give intermediate P18 (1.17 g, quant.) as a colorless solid.

To a mixture of 4-chlorophenol (50 g, 0.39 mol) and t-BuOH (57.6 g, 0.78 mol) was added conc. H₂SO₄ (40 mL) and the solution was stirred at rt for 48 h, poured into ice-water and extracted with EA twice. The combined organic layers were washed with water (3x) and brine consecutively, dried over Na₂SO₄, filtered, concentrated and purified by CC (PE/EA = 40/1) to give compound P19a (48.5 g, 68%) as a colorless solid.

To a solution of compound P19a (32.0 g, 174 mmol) and pyridine (22.5 mL, 278 mmol) in dry DCM (500 mL) was added a solution of Tf₂O (35.5 mL, 209 mmol) in dry DCM (150 mL) under ice cooling and the solution was stirred for 4 h at rt, poured into 1M HCI and extracted with DCM. The organic layer was washed with brine, dried over Na₂SO₄, filtered, concentrated and purified by CC (PE/EA = 10/1) to give compound P19b (40.0 g, 82%) as a pale yellow solid.

A solution of compound P19b (40.0 g, 142 mmol), dppp (5.0 g, 12 mmol), Pd(OAc)₂ (2.7 g, 12 mmol) and NEt₃ (150 mL, 1.1 mol) in a mixture of MeOH (300 mL) and DMSO (400 mL) was stirred overnight at 55°C under an atmosphere of CO. Water and EA were added and the organic layer was separated, washed with water twice and brine, dried over Na₂SO₄, filtered, concentrated and purified by CC (PE/EA = 8/1) to give compound P19c (27.1 g, 84%) as a colorless solid.

To a stirred solution of compound P19c (542 mg, 2.40 mmol) in a mixture of DMSO (6 mL) and H₂O (2 drops) was added t-BuOK (538 mg, 4.8 mmol) and this mixture was stirred at 85°C for 4 h, adjusted to pH = 2-3 with 1N HCl and then extracted with EA (3x). The combined organic layers were washed with water (3x) and brine consecutively, dried over Na₂SO₄, filtered, concentrated and purified by CC (PE/EA = 2/1) to give compound P19d (404 mg, 80%) as a yellow solid.

A solution of compound P19d (404 mg, 1.91 mmol), piperidine (244 mg, 2.87 mmol), HATU (870 mg, 2.29 mmol) and DIPEA (616 mg, 4.78 mmol) in DMF (5 mL) was stirred at rt for 20 min, quenched with water and extracted with EA twice. The combined organic layers were washed with water (3x) and brine consecutively, dried over Na₂SO₄, filtered, concentrated and purified by prep. TLC (PE/EA = 1/1) to give compound P19e (550 mg, 97%) as a yellow solid.

A stirred solution of PCy₃ (100 mg, 0.35 mmol) and Pd(dba)₂ (200 mg, 0.35 mmol) in 1,4-dioxane (20 mL) was stirred at rt for 30 min, then compound P19e (550 mg, 1.97 mmol), P₂Bin₂ (767 mg, 2.17 mmol) and KOAc (546 mg, 1.90 mmol) was added and the solution was heated at 90°C for 3 h, diluted with water and extracted with EA. The organic layer was washed with brine, dried over Na₂SO₄, filtered and concentrated to give compound P19 (159 mg, 22%) as a colorless solid.

To an oven dried 100 mL 3-neck flask was added 1,3-dibromo-5-(tert-butyl)benzene (500 mg, 1.72 mmol) in dry THF (30 mL) under N₂ and the mixture was cooled to -78°C. n-BuLi (2.5M, 1 mL) was added and the mixture was stirred at -78°C for 1 h. Then cyclobutanone (181 mg, 2.58 mmol) was added. After the reaction was complete (monitored by LC-MS) the mixture was quenched with aq. NH₄Cl and extracted with EA. The organic layer was dried over MgSO₄, filtered and evaporated to give compound P23a (243 mg, 50%) as a yellow solid.

To the mixture of compound P23a (243 mg, 0.86 mmol) in DCM (20 mL) was added TFA (3 mL) and the mixture was stirred at rt. Triethylsilane (200 mg, 1.72 mmol) was added and the mixture was stirred overnight, diluted with water (20 mL) and extracted with EA (3x 20 mL). The organic layer was washed with brine, dried over Na₂SO₄ and concentrated to give compound P23b (150 mg, 66%) as a colorless solid.

To a mixture of compound P23b (133 mg, 0.50 mmol), B₂Pin₂ (152 mg, 0.60 mmol) and KOAc (98 mg, 1.00 mmol) in 1,4-dioxane (10 mL) under Ar was added Pd(dppf)Cl₂ (0.03 eq) and the mixture was heated at 80°C overnight, diluted with water (20 mL) and extracted with EA (3x 20 mL). The organic layer was washed with brine, dried over Na₂SO₄, concentrated and purified by CC (hexane/EA = 20/1) to give compound P23 (110 mg, 70%) as colorless solid.

To a mixture of 2-(3-Bromo-5-(tert-butyl)phenyl)propan-2-ol [synthesis described in WO2012/139775] (190 mg, 0.7 mmol) in DMF (10 mL) was added NaH (60%, 20 mg, 1.2 mmol) and the mixture was stirred at rt for 10 min. Then Mel (423 mg, 3.0 mmol) was added and the mixture was stirred overnight, diluted with water (50 mL) and extracted with EA (3x 50 mL). The organic layer was washed with brine, dried over Na₂SO₄, concentrated and purified by CC (hexane/EA = 10/1) to give compound P30a (125 mg, 64%) as a colorless solid.

To a mixture of compound P30a (128 mg, 0.45 mmol), B₂Pin₂ (137 mg, 0.54 mmol) and KOAc (88 mg, 0.9 mmol) in 1,4-dioxane (25 mL) was added Pd(dppf)Cl₂ (0.03 eq) under Ar and the mixture was heated at 80°C overnight, diluted with water (50 mL) and extracted with EA (3x 50 mL). The organic layer was washed with brine, dried over Na₂SO₄, concentrated and purified by CC (hexane/EA = 5/1) to give compound P30 (78 mg, 52%) as a colorless solid.

A mixture of 1-(3-Bromo-5-(tert-butyl)phenyl)ethanone [synthesis as described in WO2012/139775] (510 mg, 2.0 mmol) and morpholine (208 mg, 2.4 mmol) in DCE (30 mL) was stirred at 0°C for 1 h. Then NaBH(OAc)₃ (845 mg, 4.0 mmol) was added at this temperature and the mixture was stirred overnight, diluted with aq. NH₄Cl (50 mL) and extracted with EA (3x 50 mL). The organic layer was washed with brine, dried over Na₂SO₄, concentrated and purified by CC (hexane/EA = 8/1) to give compound P31a (172 mg, 26%) as a colorless solid.

To a mixture of compound P31a (163 mg, 0.5 mmol), B₂Pin₂ (152 mg, 0.6 mmol) and KOAc (98 mg, 1.0 mmol) in 1,4-dioxane (25 mL) under Ar was added Pd(dppf)Cl₂ (0.03 eq). The mixture was heated at 80°C overnight, diluted with water (50 mL) and extracted with EA (3x 50 mL). The organic layer was washed with brine, dried over Na₂SO₄, concentrated and purified by CC (hexane/EA = 5/1) to give compound P31 (78 mg, 42%) as a colorless solid.

To a mixture of 1,3-dibromo-5-(tert-butyl)benzene (876 mg, 3.0 mmol) in THF (10 mL) was added tert-BuLi (2.5 M, 2.4 mL, 6.0 mmol) at -78°C and the mixture was stirred for 1 h at this temperature. Then DMF (222 mg, 3.0 mmol) was added at this temperature and stirred for 2 h., diluted with aq. NH₄Cl (50 mL) and extracted with EA (3x 50 mL). The organic layer was washed with brine, dried over Na₂SO₄, concentrated and purified by CC (hexane/EA = 5/1) to give compound P32a (452 mg, 63%) as a colorless solid.

A mixture of compound P32a (450 mg, 1.87 mmol) and morpholine (194 mg, 2.24 mmol) in DCE (30 mL) was stirred at 0°C for 1 h. Then NaBH(OAc)₃ (561 mg, 2.66 mmol) was added at this temperature and then stirred overnight, diluted with aq. NH₄Cl (50 mL) and extracted with EA (3x 50 mL). The organic layer was washed with brine, dried over Na₂SO₄, concentrated and purified by prep. TLC to give compound P32b (142 mg, 28%) as a colorless solid.

To a mixture of compound P32b (145 mg, 0.46 mmol) and B₂Pin₂ (152 mg, 0.6 mmol) and KOAc (98 mg, 1.0 mmol) in 1,4-dioxane (25 mL) was added Pd(dppf)Cl₂ (0.03 eq) under Ar and the mixture was heated at 80°C overnight, diluted with water (50 mL) and extracted with EA (3x 50 mL). The organic layer was washed with brine, dried over Na₂SO₄, concentrated and purified by prep. HPLC to give P32 (80 mg, 54%) as a colorless solid.

To a solution of methyl 3-bromo-5-iodobenzoate (3.40 g, 10 mmol) in 1,4-dioxane (20 mL) was added Pd(PPh₃)₄ (300 mg, 0.26 mmol), prop-1-en-2-yl boronic acid (1.0 g, 12 mmol), K₂CO₃ (2.8 g, 20 mmol) and H₂O (1 mL) under N₂. The mixture was stirred overnight at 90°C, concentrated and purified by CC (PE/EA = 6/1) to give compound P33a (1.9 g, 71%) as a solid.

To a solution of Et₂Zn (4 mL of 1.0M solution in hexanes, 4.0 mmol) in dry DCM (4 mL) at 0°C was added freshly distilled TFA (0.36 mL, 4.0 mmol) in DCM (4 mL) very slowly (ca. 30 min). The gray mixture was stirred at 0°C for 20 min at which time CH₂I₂ (0.4 mL, 4.0 mmol) dissolved in DCM (4 mL) was introduced by cannulation. The resulting slurry was stirred for 20 min before the addition of compound P33a (0.53 g, 2.0 mmol) dissolved in DCM (3 mL). The slurry was allowed to warm to rt over 30 min, quenched by the addition of sat. aq. NH₄Cl (5 mL) and the layers were separated. The aq. layer was extracted with hexane (2x) and dried over MgSO₄. Evaporation and purification by CC (PE/EA = 7/1) afforded compound P33b (300 mg, 46%) as a colorless oil.

Compound P33b (270 mg, 1.0 mmol) and LiOH (50 mg, 2.0 mmol) were mixed in THF (3 mL) and H₂O (3 mL). The mixture was stirred for 10 h, then the pH was adjusted to pH 3 with aq. HCI and extracted with EA (3x 10 mL). The organic layer was dried and concentrated to afford the crude product P33c (250 mg, quant.).

To a solution of compound P33c (250 mg, 1.0 mmol) in DMF (5 mL) was added HATU (380 mg, 1.0 mmol), MeNH^tBu (174 mg, 2.0 mmol) and Et₃N (202 mg, 2.0 mmol) and the mixture was stirred overnight. After removal of the solvents the crude product was purified with prep. HPLC to afford compound P33d (300 mg, 95%).

To a suspension of compound P33d (323 mg, 1.0 mmol), B₂Pin₂ (380 mg, 1.5 mmol), KOAc (290 mg, 3.0 mmol) in 1,4-dioxane (5 mL) was added Pd(dppf)Cl₂ (20 mg) under N₂. The mixture was heated to 100°C for 16 h, concentrated and purified by CC (PE/EA = 4/1) to afford compound P33 (200 mg, 68%) as a colorless solid.

Using similar procedures as described in Preparative Example P33, the following compounds were prepared: # Structure # Structure P33/1 P33/2

To the solution of 1,3-dibromo-5-(trifluoromethoxy)benzene (654 mg, 2.06 mmol) in toluene (6 mL) were added tri-n-butyl-1-ethoxyvinyl tin (969 mg, 2.68 mmol) and Pd(PPh₃)₂Cl₂ (147 mg 0.21 mmol) under N₂. The mixture was stirred at 95°C for 3 h, concentrated and dissolved in 1,4-dioxane and 2M HCl. The mixture was stirred rapidly at 25°C for 1 h and then extracted with EA (3x 20 mL). The organic layer was washed with brine, dried over Na₂SO₄, concentrated and purified by CC to give compound P36a (580 mg, 55%).

An oven dried flask was charged with DCM (5 mL) and TiCl₄ (763 mg, 4.06 mmol), Zn(CH₃)₂ (1M, 4 mL) was added and the solution was cooled to -30°C and stirred at constant temperature for 0.5 h. Then a solution of compound P36a (572 mg, 2.03 mmol) in DCM was added dropwise and the mixture was allowed to warm to 0°C over a period of 40 min, stirred at rt for 2 h, 45 min at 45°C and 40°C overnight, diluted with water (20 mL) and extracted with EA (3x 20 mL). The organic layer was washed with brine, dried over Na₂SO₄ and concentrated to give product P36 (180 mg, 30%) as a yellow oil.

To a solution of 2-(tert-butyl)aniline (14.9 g, 100 mmol) was added a solution of NBS (17.8 g, 100 mmol) in DMF at rt. The mixture was stirred overnight at rt, diluted with water (30 mL) and extracted with Et₂O (3x 250 mL). The organic layer was washed with brine, dried over Na₂SO₄, concentrated and purified by CC to give compound P38a (19 g, 83%).

To a solution of compound P38a (5.0 g, 21.9 mmol), hydroxylamine hydrochloride (5.48 g, 78.9 mmol) and sodium sulfate (24.9 g, 175 mmol) in H₂O (150 mL) and 2M HCl (7.4 mL) at rt under N₂ was added chloral hydrate (3.88 g, 26.3 mmol). The resulting solution was stirred at 55°C for 18 h, cooled to rt, diluted with water (100 mL) and extracted with EA (3x 50 mL). The combined organic layers were concentrated to give P38b (5 g) as a viscous oil.

A solution of compound P38b (5 g, 16.7 mmol) in conc. H₂SO₄ (30 mL) was stirred at 80°C for 1 h, cooled to rt, poured onto crushed ice (200 mL) and allowed to stand for 30 min. The precipitate was collected by filtration, washed with water (3x) and dried under vacuum to yield compound P38c (2 g) as a yellow solid.

KOH (796 mg, 14.2 mmol) was added into a mixture of compound P38c (2 g, 7.1 mmol), ethyleneglycol (20 mL) and hydrazine hydrate (0.5 g, 9.93 mmol). The mixture was stirred at 80°C for 3h, cooled to rt and poured into ice cold water. The pH of the mixture was adjusted to pH 1-2 with 12M HCl and the mixture was stirred at rt for 12 h and extracted with EA. The organic phase was evaporated to give compound P38d (1.5 g) as a yellow solid.

To a solution of compound P38d (1.0 g, 3.73 mmol) in DMF (20 mL) was added a solution of CH₃I (0.93 mL) in DMF at 0°C. The mixture was stirred overnight at rt, diluted with water (100 mL) and extracted with Et₂O (3x 100 mL). The organic layer was washed with brine, dried over Na₂SO₄, concentrated and purified by CC to give compound P38e (500 mg, 43% over 4 steps) as a light yellow solid.

A solution of compound P38e (760 mg, 2.45 mmol) was treated as described for Example P33, Step 5 to give compound P38 (750 mg, 86%) as a colorless solid.

To a solution of 4-bromo-2-(difluoromethoxy)aniline (4.50 g, 18.9 mmol) in AcOH (20 mL) was added conc. HCl (10 mL) at rt and the solution was cooled to 5°C. Then a solution of NaNO₂ (1.45 g, 21.0 mmol) in H₂O (15 mL) was added and the solution was stirred at 0°C for 1 h. The resulting diazonium salt was added to a mixture of saturated solution of SO₂ in AcOH (100 mL) and CuCl₂·2HO (3.61 g, 21.0 mmol) in H₂O (50 mL) at rt and the solution was stirred at rt for 30 min, poured into water and extracted with DCM twice. The combined organic layers were purified by CC (PE) to give compound P45a (2.1 g, 35%) as an oil.

To a solution of compound P45a (2.10 g, 6.53 mmol) and pyridine (1.19 g, 15.1 mmol) in CH₂Cl₂ (20 mL) was added tert-butylamine (511 mg, 7.00 mmol) at rt and the mixture was stirred for 1 h, then washed with water and brine, dried over Na₂SO₄, filtered, concentrated and purified by CC (PE/EA = 4/1) to give compound P45b (2.16 g, 92%) as a colorless solid.

A solution of compound P45b (2.16 g, 6.03 mmol) was treated as described for Example P33, Step 5 to give compound P45 (1.25 g, 51%) as a colorless solid.

Using similar procedures as described in Preparative Example P45, the following compounds were prepared: # Structure # Structure P45/1 P45/2 P45/3 P45/4 P45/5 P45/6 P45/7 P45/8 P45/9 P45/10 P45/11 P45/12 P45/13 P45/14 P45/15 P45/16 P45/17

To a solution of methyl 5-bromo-1-(cyclohexylmethyl)-1H-pyrrole-3-carboxylate (1.8 g, 6.0 mmol) (prepared similar as described in Example 1) and DMF (3 mL) in 1,2-dichloroethane (50 mL) was added POCl₃ (1.38 g, 9.0 mmol) and the solution was stirred for 1 h, then warmed to 80°C overnight, diluted with water (50 mL), basified with 2M NaHCO₃ and extracted with EA (3x 50 mL). The combined organic layer was washed with brine, dried over Na₂SO₄, filtered, evaporated and purified by CC (EA/PE = 1/10) to give compound P49a (1.1 g, 58%).

To a solution of P49a (1.1 g, 3.5 mmol) in MeOH (3 mL) at rt was added NaBH₄ (152 mg, 4 mmol) and the resulting solution was stirred at this temperature for 20 min, diluted with water (50 mL) and extracted with EA (3x 50 mL). The combined layer was concentrated to give compound P49b (1.03 g, 89%).

Compound P49b (200 mg, 0.61 mmol) was saponified and then coupled with tetrahydro-2H-pyran-4-amine similar as described in Example 1 (Step 7 and 8) to give compound P49 (210 mg, 86%) as a colorless solid.

To a solution of compound P49b (600 mg, 1.82 mmol) in CH₂Cl₂ at -70°C was added bis(2-methoxyethyl)aminosulfur trifluoride (400 mg, 1.82 mmol) and the resulting solution was stirred at this temperature for 1 h, then warmed to rt for additional 1 h, diluted with water (50 mL) and extracted with EA (3x 50 mL). The combined organic layer was concentrated and purified by CC (EA/PE = 1/10) to give compound P50a (90 mg, 15%).

Compound P50a (90 mg, 0.61 mmol) was saponified and then coupled with tetrahydro-2H-pyran-4-amine similar as described in Example 1 (Step 7 and 8) to give compound P50 (82 mg, 77%) as a colorless solid.

To a solution of methyl 5-bromo-1-(cyclohexylmethyl)-1H-pyrrole-3-carboxylate (600 mg, 1.63 mmol) (prepared similar as described in Example 1) in dry THF (50 mL) was added NCS (250 mg, 1.87 mmol) at rt under nitrogen. The reaction was stirred at 55°C for overnight and quenched with a cold aq. solution of NH₄Cl. The organic layer was separated and the aqueous layer extracted repeatedly with EA. The combined organic layer was washed with brine, dried over Na₂SO₄, filtered, evaporated and purified by CC (EA/PE = 1/3) to give compound P51 (510 mg, 80%).

To a solution of 2-(4-iodo-2-(trifluoromethyl)phenyl)acetic acid (2.00 g, 6.06 mmol) in DCM (20 mL) were added (COCl)₂ (1.54 g, 12.1 mmol) and DMF (1 drop) in one portion at rt and the mixture was stirred at rt for 1 h and concentrated to give compound P53a (2.00 g, 95%) as a colorless oil.

To a solution of tert-butylamine (876 mg, 12.0 mmol) in DCM (10 mL) was added TEA (2.54 g, 24.0 mmol) and the mixture was stirred at rt for 30 min, then compound P53a (2.00 g, 5.85 mmol) in DCM (10 mL) was added and the mixture was stirred at rt overnight, concentrated and purified by CC (PE/EA = 1/5) to give compound P53b (1.20 g, 52%) as a yellow solid.

A solution of compound P53b (500 mg, 1.30 mmol), compound P18a (535 mg, 1.40 mmol) K₂CO₃ (450 mg, 3.38 mmol), TBAB (10 mg) and Pd(PPh₃)₂Cl₂ (10 mg) in a mixture of 1,4-dioxane (10 mL) and water (5 mL) in a sealed tube was irradiated by microwaves at 100°C for 100 min, concentrated and purified by CC (PE/EA = 1/10) to afford compound P53 (100 mg, 15%) as a colorless solid.

To a solution of BnOH (2.16 g, 20.0 mmol) in DCM (20 mL) was added TEA (3.54 g, 35.0 mmol) and the mixture was stirred at rt for 30 min. Then a solution of compound P53a (3.48 g, 10.0 mmol) in DCM (15 mL) was added and the mixture was stirred at rt overnight, concentrated and purified by CC (PE/EA = 1/15) to give compound P54a (2.65 g, 79%) as a yellow oil.

To a solution of NaH (880 mg, 22.1 mmol) in THF (30 mL) was added compound P54a (2.65 g, 6.30 mmol) and the mixture was stirred at rt for 30 min. Then Mel (3.10 g, 22.1 mmol) was added and the mixture was stirred at rt overnight, quenched with water and extracted with EA. The organic layer was dried with MgSO₄, filtered, concentrated and purified by CC (PE/EA = 1/15) to give compound P54b (900 mg, 32%) as a yellow oil.

A solution of compound P54b (900 mg, 2.00 mmol), compound P18a (750 mg, 2.00 mmol) K₂CO₃ (690 mg, 5.00 mmol), TBAB (10 mg) and Pd(PPh₃)₂Cl₂ (10 mg) in a mixture of dioxane (10 mL) and water (5 mL) in a sealed tube was irradiated with microwaves at 100°C for 100 min, concentrated and purified by CC (PE/EA = 1/8) to afford compound P54c (400 mg, 36%) as a colorless solid.

To a solution of compound P54c (400 mg, 0.75 mmol) in EtOH (10 mL) was added Pd/C (10%, 40 mg) in one portion at rt and the mixture was stirred under H₂ (50 psi) for 5 h, filtered; concentrated and purified by CC (PE/EA = 5/1) to give compound P54d (300 g, 90%) as a colorless solid.

To a solution of compound P54d (300 mg, 0.63 mmol) in DCM (10 mL) were added (COCl)₂ (159 mg, 1.25 mmol) and DMF (1 drop) in one portion at rt and the mixture was stirred for 1 h and concentrated to give compound P54e (300 mg, 95%) as a colorless oil.

To a solution of tert-butylamine (91 mg, 1.25 mmol) in DCM (5 mL) was added TEA (190 mg, 1.88 mmol) and the mixture was stirred at rt for 30 min. Then a solution of compound P54e (300 mg, 0.63 mmol) in DCM (5 mL) was added and the mixture was stirred at rt overnight, concentrated and purified by CC (PE/EA = 1/5) to give compound P54 (100 mg, 30%) as a yellow solid.

To a solution of 4-bromo-N-(tert-butyl)-2-(trifluoromethyl)benzenesulfonamide (10.5 g, 29.2 mmol) in dry THF (100 mL) was added n-BuLi (2.5M in hexane, 12.0 mL, 30.0 mmol) dropwise over 10 min at -78°C under N₂, then the resulting solution was stirred at -78°C for 1 h. N-Methoxy-N-methylacetamide (4.63 g, 45 mmol) was added, after stirring for a further 10 min, the cooling bath was removed and the mixture was allowed to warm to rt and then stirred at rt for 2 h, quenched with 1M HCl and extracted with EA (3x 60 mL). The combined organic phase was washed with brine, dried over Na₂SO₄, filtered, concentrated and purified by CC (PE/EA = 3/1) to give compound P55a (3.7 g, 39%) as a colorless solid.

To a solution of compound P55a (3.7 g, 11.5 mmol) in dry THF (100 mL) was added PhNMe₃Br₃ (4.32 g, 11.5 mmol) dropwise at 0°C and the solution was stirred for 4 h at rt, partially concentrated, washed with water twice and brine consecutively, dried over Na₂SO₄, filtered, concentrated and purified by CC (PE/EA = 2/1) to give compound P55b (2.9 g, 63%) as yellow oil.

A solution of 3,3-difluorocyclobutylmethylamine (0.40 g, 2.5 mmol), phenylmethyl 3-oxobutanoate (1.05 g, 5.5 mmol), DIEA (0.71g, 5.5 mmol) in DMF (5 mL) was placed in a sealed tube in a hot oil bath (150°C) and then stirred for 15 min. A solution of compound P55b (1.21 g, 3.0 mmol) in DMF (2 mL) was added to the hot resulting solution at 100°C. The solution was heated to 180°C quickly and stirred for another 15 min at 180°C, cooled to rt, diluted with water and extracted with EA. The organic layer was washed with water and brine, dried over Na₂SO₄, filtered, concentrated and purified by CC (PE/EA = 5/1) to give compound P55c (140 mg, 9%) as a brown oil.

A suspension of compound P55c (130 mg, 0.22 mmol) and 10% Pd/C (50 mg) in MeOH (15 mL) was stirred under 1 atmosphere of H₂ at rt for 2 h, filtered, concentrated and purified by CC (DCM/MeOH = 15/1) to give compound P55 (65 mg, 59%) as a colorless solid.

Using similar procedures at those described in Preparative Example P55, the following compounds were prepared: # Structure # Structure P55/1 P55/2 P55/3

To a solution of 4-bromo-2-(trifluoromethyl)aniline (50 g, 22 mmol), hydroxylamine hydrochloride (5.48 g, 78.9 mmol) and sodium sulfate (24.9 g, 175 mmol) in H₂O (150 mL) and 2M HCl (7.4 mL) at rt under N₂ was added chloral hydrate (3.88 g, 26.3 mmol) and the solution was stirred at 55°C for 18 h, cooled to rt, diluted with water (100 mL) and extracted with EA (3x 50 mL). The combined layer was concentrated to give compound P56a (5.0 g) as a viscous oil.

A solution of P56a (5.0 g, 16.7 mmol) in conc. H₂SO₄ (30 mL) was stirred at 80°C for 1 h, cooled to rt, poured into crushed ice (200 mL) and allowed to stand for 30 min. The precipitate was collected by filtration, washed with water (3x) and dried to yield compound P56b (2.0 g) as a yellow solid.

KOH (796 mg, 14.2 mmol) was added into a mixture of P56b (2.0 g, 7.09 mmol), ethyleneglycol (20 mL) and hydrazine hydrate (98%, 0.5 g, 10 mmol), stirred at 80°C for 3 h, cooled to rt and poured into ice cold water. The pH of the mixture was adjusted to pH 1-2 with 12M HCl and stirred at rt for 12 h and extracted with EA. The organic phase was collected and evaporated to give compound P56c (1.5 g) as a yellow solid.

To a solution of compound P56c (1.0 g, 3.7 mmol) in DMF (20 mL) was added a solution of CH₃I (0.93 mL) in DMF at 0°C. The mixture was stirred at rt overnight, diluted with water (100 mL) and extracted with Et₂O (3x100 mL). The organic layer was washed with brine, dried over Na₂SO₄, concentrated and purified by CC to give compound P56d (500 mg, 43%) as a light yellow solid.

A solution of compound P56d (760 mg, 2.45 mmol) was treated as described for Example P33, Step 5 to give compound P56 (750 mg, 86%) as a colorless solid.

A solution of 2-fluoro-4-iodo-6-(trifluoromethyl)pyridine (100 mg, 0.34 mmol) and neopentyl amine (150 mg, 1.70 mmol) in MeCN (1 mL) in a sealed tube was irradiated by microwaves at 130°C for 30 min, cooled, diluted with water and extracted with EA. The organic layer was washed with brine, dried, concentrated and purified by CC (PE/EA = 20/1) to give compound P57 (100 mg, 83%) as a colorless solid.

To a solution of NaOEt in EtOH (prepared from sodium (1.29 g, 56.1 mmol) and EtOH (40 mmol)) was added 2-(trifluoromethyl)benzene-1-thiol (5.0 g, 28.1 mmol) and neopentyl 4-methylbenzenesulfonate (6.80 g, 28.1 mmol) and the solution was stirred at reflux under N₂ for 20 h, cooled to rt and the formed solid was filtered off. The cake was washed with Et₂O and the combined filtrate was concentrated and diluted with water and ether consecutively. The organic phase was washed with water, dried over Na₂SO₄, filtered, concentrated and purified by CC (petroleum) to give compound P58a (4.55 g, 65%) as a colorless solid.

To a solution of compound P58a (1.0 g, 4.0 mmol) in dry DCM (15 mL) was added Br₂ (640 mg, 4.0 mmol) at rt and the solution was stirred for 2 h, washed with water, sat. sodium thiosulfate and brine consecutively, dried and concentrated to give compound P58b (1.27 g, 97%) as a colorless solid.

To a solution of compound P58b (1.27 g, 3.9 mmol) in DCM (20 mL) was added 3-chloroperoxybenzoic acid (3.0 g, 11.7 mmol) at -10°C and the solution was stirred at rt overnight, diluted with DCM and water and the two layers were separated. The organic layer was washed with sat. NaHCO₃ twice and brine consecutively, dried over Na₂SO₄, filtered, concentrated and purified by CC (PE/EA = 25/1) to give compound P58c (700 mg, 47%) as a colorless solid.

Compound P58c (359 mg, 1.0 mmol) was treated similar as described in Preparative Example P54, Step 3 to give compound P58 (500 mg, 95%) as a yellow oil.

To a solution of bisbenzylamine (140 g, 0.70 mol) in THF (1.0L) was added n-BuLi (2.5M, 280 mL, 0.7 mol) dropwise under N₂ at -30°C, then the reaction solution was stirred at this temperature for 10 min. 2-Fluorobenzoic acid (50 g, 0.35 mol) in THF (500 mL) was added dropwise at -30°C and the solution was heated to 0°C for 2 h, quenched with water (100 mL), concentrated, treated with conc. HCl until pH 1 and extracted with DCM (3x 500 mL). The organic layer was concentrated and recrystallized from Et₂O to give compound P59a (40 g, 36%) as colorless solid. ¹H-NMR (300 MHz, CDCl₃) δ: 4.16 (s, 4H), 7.15-7.61 (m, 13H), 8.15-8.18 (m, 1H).

The solution of compound P59a (20 g, 63 mmol), K₂CO₃ (26 g, 189 mmol), CH₃I (14 g, 94 mmol) and DMF (200 mL) was stirred at rt for 2 h, diluted with Et₂O (1 L) and the organic phase was washed with water (3x 500 mL) and brine consecutively, dried over Na₂SO₄, filtered and concentrated to give compound P59b (20 g, 96%) as colorless oil. ¹H-NMR (300 MHz, CDCl₃) δ: 3.89 (s, 3H), 4.25 (s, 4H), 6.94-6.99 (m, 2H), 7.21-7.37 (m, 11H), 7.69-7.72 (m, 1H).

To a solution of Ti(Oi-Pr)₄ (99.6 g, 0.36 mol) in dry Et₂O (1.0 L) was added EtMgBr (2M in THF, 540 mL, 1.08 mol) dropwise at -68°C under N₂ and the solution was stirred at this temperature for 1.5 h. To the reaction solution was added compound P59b (60.0 g, 0.18 mol) in dry Et₂O (0.5 L) at -68°C and then the solution was stirred overnight at rt, quenched carefully with 1M HCl (500 mL) at 0°C and separated. The aq. layer was extracted with Et₂O (3x 300 mL). The combined organic layers were washed with brine, dried over Na₂SO₄, filtered, concentrated and purified by CC (PE/EA = 100/1) to give compound P59c (9.0 g, 15%) as colorless oil. ¹H-NMR (400 MHz, CDCl₃) δ: 0.96-0.99 (m, 2H), 1.11-1.15 (m, 2H), 4.18 (s, 4H), 6.98-7.31 (m, 14H), 7.96 (s, 1H).

To a solution of compound P59c (5.8 g, 17.6 mmol), CH₃I (3.7 g, 26.4 mmol) in dry THF (20 mL) was added NaH (60%, 1.0 g, 26.4 mmol) in portions at 0°C under N₂ and the solution was stirred at rt overnight, quenched with water (50 mL) and extracted with EA (3x 150 mL). The combined organic layers were washed with brine, dried over Na₂SO₄, filtered, concentrated and purified by CC (PE/EA = 100/1) to give compound P59d (5.0 g, 83%) as colorless oil. ¹H-NMR (300 MHz, CDCl₃) δ: 0.95-0.99 (m, 2H), 1.22-1.26 (m, 2H), 3.24 (s, 3H), 4.32 (s, 4H), 6.96-7.45 (m, 14H).

A solution of compound P59d (4.0 g, 11.6 mmol), HCO₂NH₄ (7.3 g, 116 mmol), Pd/C (0.5 g) in MeOH (20 mL) was heated to 45°C for 5 h, cooled to rt, filtered and the filtrate was concentrated. The residue was dissolved in EA (200 mL) and washed with water (3x 100 mL). The organic layer was washed with brine, dried over Na₂SO₄, filtered and concentrated to give crude product P59e (1.5 g, 75%) as colorless oil. ¹H-NMR (300 MHz, CDCl₃) δ: 0.90-0.93 (m, 2H), 1.09-1.13 (m, 2H), 3.16 (s, 3H), 6.66-6.69 (m, 2H), 7.10-7.14 (m, 2H).

To a solution of compound P59e (2.0 g, 12.3 mmol) in MeCN (10 mL) was added NBS (2.18 g, 12.3 mmol) in three portions at 0°C under N₂ and the solution was stirred at rt overnight, concentrated and purified by CC (PE/EA = 100/1) to give compound P59f (2.0 g, 70%) as yellow oil. ¹H-NMR (400 MHz, CDCl₃) δ: 0.87-0.90 (m, 2H), 1.07-1.11 (m, 2H), 3.14 (s, 3H), 4.32 (br s, 2H), 6.55-6.57 (d, J = 8.0 Hz, 1H), 7.16-7.20 (m, 2H).

A solution of compound P59f (1.0 g, 4.0 mmol) in MeCN (40 mL) was cooled to 0-5°C, AcOH (4.0 mL) and conc. HCl (2.0 mL) were added consecutively and then NaNO₂ (304 mg, 4.4 mmol) in water (3 mL) over 10 min at 0-5°C. After stirring 20 min, SO₂ was bubbled in over 40 min while keeping the temperature below 7°C. A solution of CuCl₂·2H₂O (818 mg, 2.4 mmol) in water (3 mL) was added and the solution was allowed to warm to rt and stirred for 1 h, extracted with EA, washed with aq. NaHCO₃ (2x 100 mL) and water (2x 100 mL) consecutively, dried over Na₂SO₄, filtered and concentrated to give product P59g (800 mg, 50%) as yellow solid.

A solution of compound P59g (800 mg, 2.46 mmol), 2-methylprop-2-ylamine (269 mg, 3.69 mmol), Et₃N (497 mg, 4.92 mmol) and MeCN (5 mL) was stirred at rt overnight, concentrated and purified by CC (PE/EA = 80/1) to give compound P59h (400 mg, 46%) as yellow solid. ¹H-NMR (300 MHz, CDCl₃) δ: 1.15-1.23 (m, 2H), 1.25 (s, 9H), 1.28-1.33 (m, 2H), 3.22 (s, 3H), 5.87 (s, 1H), 7.59 (s, 1H), 7.61-7.62 (m, 2H), 8.01-8.04 (d, J = 12.0 Hz, 1H).

Compound P59h (200 mg, 0.55 mmol) was treated similar as described for Example P33, Step 5 to give compound P59 (150 mg, 67%) as colorless solid. ¹H-NMR (400 MHz, CDCl₃) δ: 1.18-1.21 (m, 2H), 1.23 (s, 9H), 1.26-1.27 (m, 2H), 1.36 (s, 12H), 3.19 (s, 3H), 5.97 (s, 1H), 7.81 (s, 1H), 7.86-7.88 (d, J = 8.0 Hz, 1H), 8.12-8.14 (d, J = 8.0 Hz, 1H).

To the solution of 4-bromo-2-fluoroaniline (6.0 g, 31.6 mmol), AcOH (9 mL) and conc. HCl (5 mL) in MeCN (180 mL) was added NaNO₂ (2.6 g, 37.9 mmol) over 10 min at < 5°C and the solution was stirred for 30 min at this temperature. SO₂ gas was bubbled in over 30 min. Then a solution of CuCl₂·H₂O (6.4 g, 37.9 mmol) in H₂O (5 mL) was added and the solution was stirred for additional 2 h at rt, concentrated and diluted with EA. The organic layer was washed with water and brine consecutively, dried over Na₂SO₄, filtered, concentrated and purified by CC (PE/EA = 40/1) to give compound P60a (3.7 g, 43%) as colorless oil.

To a solution of compound P60a (3.7 g, 13.6 mmol) and pyridine (2 mL) in DCM (40 mL) was added 2-methylprop-2-ylamine (3.0 g, 40.7 mmol) at 0°C and the solution was stirred at this temperature for 1 h, concentrated and purified by CC (PE/EA = 40/1) to give compound P60b (2.2 g, 53%) as a colorless solid.

To a solution of 2,2-dimethylpropan-1-ol (1.14 g, 12.9 mmol) in dry DMF (15 mL) was added NaH (60% in oil, 413 mg, 10.3 mmol) at 0°C under N₂ and the solution was stirred at this temperature for 40 min. Then compound P60b (800 mg, 2.58 mmol) was added and the solution was stirred at 90°C for additional 2 h, diluted with water and extracted with EA (3x). The combined organic layers were washed with water (3x) and brine consecutively, dried over Na₂SO₄, filtered, concentrated and purified by CC (PE/EA = 10/1) to give compound P60c (925 mg, 95%) as a colorless solid.

A solution of compound P60c (600 mg, 1.59 mmol) was treated as described for Example P33, Step 5 to give compound P60 (380 mg, 60%) as a colorless solid.

To a solution of ethyl 5-(4-(N-(tert-butyl)sulfamoyl)-3-(trifluoromethyl)phenyl)-1-(cyclohexylmethyl)-1H-pyrrole-3-carboxylate (2.6 g, 5.06 mmol) in dry THF (25 mL) was added a solution of NBS (0.9 g, 5.06 mmol) in dry THF (10 mL) at -78°C and the solution was stirred at -55°C for 2 h, quenched with water and extracted with EA. The organic layer was washed with brine, dried over Na₂SO₄, filtered, concentrated and carefully purified by CC (PE/EA = 5/1) to give compound P61a (1.08 g, 36%) as a colorless solid.

A solution of compound P61a (800 mg, 1.35 mmol), CuCN (145 mg, 1.62 mmol) and KI (10 mg) in DMF (10 mL) was stirred at 120°C overnight under N₂, cooled to rt and diluted with 27% NH₄OH (2 mL). The resulting solution was filtered and the filtrate was extracted with EA. The organic layer was washed with brine, dried over Na₂SO₄, filtered, concentrated and purified by CC (PE/EA = 3/1) to give compound P61b (496 mg, 68%) as a colorless solid.

A mixture of compound P61b (100 mg, 0.19 mmol) and t-BuOK (38 mg, 0.40 mmol) in a mixture of DMSO and H₂O (10/1, 2 mL) was stirred at 90°C for 1 h, cooled, diluted with water, acidified with 1M HCl to pH = 6 and extracted with EA. The organic layer was washed with water and brine consecutively, dried over Na₂SO₄, filtered and concentrated to give compound P61 (67 mg, 70%) as a colorless solid.

To a cooled (ice bath) solution of compound P61b (257 mg, 0.48 mmol) in DMSO (5 mL) was added 30% H₂O₂ (0.07 mL) and K₂CO₃ (197 mg, 1.43 mmol) and the solution was stirred overnight at rt, quenched with water and extracted with EA. The organic layer was washed with brine, dried over Na₂SO₄, filtered, concentrated and purified by CC (PE/EA = 1/1) to give compound P62a (145 mg, 54%) as a colorless solid.

A mixture of compound P62a (145 mg, 0.26 mmol) and t-BuOK (89 mg, 0.79 mmol) in a mixture of DMSO and H₂O (10/1, 2 mL) was stirred at 85°C for 1 h, cooled, diluted with water, acidified with 1M HCl to pH = 6 and extracted with EA. The organic layer was washed with water and brine consecutively, dried over Na₂SO₄, filtered and concentrated to give crude compound P62 (162 mg) as a colorless solid.

To a mixture of 4-bromo-6-(tert-butyl)pyridin-2(1H)-one (1.15 g, 5.0 mmol) in benzene (65 mL) was added BnBr (855 mg, 5.0 mmol) and Ag₂CO₃ (689 mg, 2.5 mmol) successively and the mixture was stirred at 60°C overnight, cooled to rt and the solid was filtered off. The filtrate was washed with sat. NaHCO₃, dried over Na₂SO₄, concentrated and purified by CC (PE/EA = 10/1) to give compound P63a (1.39 g, 86%) as a colorless oil.

A solution of compound P63a (320 mg, 1.0 mmol), B₂Pin₂ (508 mg, 2.0 mmol), KOAc (294 mg, 3.0 mmol) and Pd(dppf)Cl₂ (73.2 mg, 0.10 mmol) in a mixture of 1,4-dioxane and DMSO (50/1, 15 mL) was stirred at 80°C under N₂ for 1 h, cooled to rt and diluted with H₂O (15 mL), extracted with EA (3x). The combined organic layers were washed with brine twice, dried over Na₂SO₄, filtered, concentrated and purified by CC (PE/EA = 10/1) to give crude compound P63b (380 mg, quant.) as a colorless solid.

A solution of compound P63b (141 mg, 0.38 mmol), ethyl 5-bromo-1-(cyclohexylmethyl)-2-methyl-1H-pyrrole-3-carboxylate (189 mg, 0.58 mmol), Cs₂CO₃ (375 mg, 1.15 mmol) and Pd(dppf)Cl₂ (73.2 mg, 0.1 mmol) in a mixture of 1,4-dioxane and H₂O (4/1, 5 mL) was stirred at 100°C under N₂ for 2 h, diluted with H₂O (15 mL) and extracted with EA (3x). The combined organic layers were washed with water and brine, dried over Na₂SO₄, filtered, concentrated and purified by CC (PE/EA = 50/1) to give compound P63c (78 mg, 42%) as a colorless solid.

To a solution of compound P63c (700 mg, 1.43 mmol) in dry DCM (30 mL) at 5°C was added anhydrous FeCl₃ (1.93 g, 7.15 mmol) and the mixture was stirred at rt for 5 h under N₂, diluted with water and extracted with EA twice. The combined organic layers were washed with brine, dried over Na₂SO₄, filtered, concentrated and purified by CC (PE/EA = 10/1) to give compound P63d (470 mg, 82%) as a colorless oil.

To a solution of compound P63d (470 mg, 1.18 mmol) and pyridine (186 mg, 2.36 mmol) in DCM (10 mL) was added Tf₂O (499 mg, 1.77 mmol) and the solution was stirred at rt for 2 h under N₂, diluted with water and extracted with DCM. The organic layer was washed with brine, dried over Na₂SO₄, filtered, concentrated and purified by prep. TLC (PE/EA = 50/1) to give compound P63e (250 mg, 41%) as a colorless oil.

A solution of compound P63e (250 mg, 0.48 mmol), 2,2-dimethylpropylamine (202 mg, 2.32 mmol), t-BuONa (178 mg, 1.86 mmol), Pd(OAc)₂ (21 mg, 0.09 mmol) and 2-dicyclohexylphosphino-2'-(N,N-dimethylamino)biphenyl (73 mg, 0.18 mmol) in toluene (10 mL) was stirred at 110°C under N₂ for 2 h, diluted with H₂O and extracted with EA (3x). The combined organic layers were washed with water and brine, dried over Na₂SO₄, filtered, concentrated and purified by CC (PE/EA = 50/1) to give compound P63f (240 mg, quant.) as a brown solid.

To a solution of compound P63f (240 mg) in a mixture of DMSO and H₂O (10/1, 11 mL) was added t-BuOK (288 mg, 2.57 mmol) and the solution was stirred at 90°C for 4 h, cooled to rt, acidified with sat. citric acid to pH = 3 and extracted with EA. The solution was dried over Na₂SO₄, filtered, concentrated and purified by prep. TLC to give compound P63 (200 mg, 89%) as a yellow oil.

To a solution of benzo[b]thiophen-7-amine (4.65 g, 30 mmol) in DCM (100 mL) was added a solution of Br₂ (4.99 g, 0.03 mL) in DCM (120 mL) at -78°C and the solution was stirred for 1.5 h at -78°C, quenched with water and extracted with DCM (3x). The combined organic layers were washed with water and brine, dried over Na₂SO₄, filtered, concentrated and purified by CC (PE/EA = 30/1) to give of compound P64a (2.38 g, 34%) as a colorless solid. ¹H-NMR (400 MHz, CD₃OD) δ: 6.62 (d, J = 8.0 Hz, 1H), 7.30 (d, J = 8.4 Hz, 1H), 7.40 (d, J = 5.2 Hz, 1H), 7.62 (d, J = 6.0 Hz, 1H).

To a solution of compound P64a (2.38 g, 10.5 mmol) in AcOH (8 mL) was added conc. HCl (24 mL) at rt and the solution was cooled to -5°C. Then a solution of NaNO₂ (1.08 g, 15.7 mmol) in H₂O (8 mL) was added and the solution was stirred at 0°C for 1 h. The resulting diazonium salt was added to a premixed solution of SO₂ in AcOH (sat., 30 mL) and CuCl₂·H₂O (1.34 g, 7.86 mmol) in H₂O (20 mL) at rt and the solution was stirred at rt for 2 h, poured into water and extracted with DCM twice. The combined organic layers were concentrated and purified by CC (PE/EA = 30/1) to give compound P64b (3.26 g, quant.) as a colorless oil.

The solution of compound P64b (3.26 g, 10.5 mmol), tert-butyl amine (2.5 mL) and pyridine (30 mL) in dry DCM (100 mL) was stirred for 1 h at rt, washed with water twice and brine consecutively, dried over Na₂SO₄, filtered, concentrated and purified by CC (PE/EA = 10/1) to give compound P64 (2.6 g, 71%) as a colorless solid. ¹H-NMR (400 MHz, CDCl₃) δ: 1.19 (s, 9H), 7.59 (d, J = 6.4 Hz, 1H), 7.67 (d, J = 6.4 Hz, 1H), 7.68 (d, J = 8.0 Hz, 1H), 7.82 (d, J = 8.0 Hz, 1H).

To a solution of ethyl 4-hydroxy-2-naphthoate (15.0 g, 58.1 mmol) and NEt₃ (11.7 g, 116 mmol) in dry DCM (300 mL) was added a solution of Tf₂O (24.5 g, 87.1 mmol) in DCM (50 mL) at 0°C and the solution was stirred for 4 h at rt, washed with H₂O and brine, dried over Na₂SO₄, filtered, concentrated and purified by CC (PE/EA = 8/1) to give compound P65a (18.0 g, 89%) as a colorless solid.

To a solution of compound P65a (13.2 g, 42.4 mmol) in dry THF (150 mL) was added MeMgBr (1M in THF, 51 mL, 51 mmol) dropwise at 0°C and the solution was stirred at 25°C for 1 h, diluted with sat. NH₄Cl and extracted with DCM twice. The combined organic layers were washed with water and brine, dried over Na₂SO₄, filtered, concentrated and purified by CC (PE/EA = 2/1) to give compound P65b (16.7 g, quant.) as a yellow oil.

A suspension of compound P65b (1.6 g, 4.8 mmol), KOAc (1.5 g, 14.4 mmol), B₂Pin₂ (1.5 g, 5.7 mmol) and Pd(dppf)Cl₂ (176 mg, 0.24 mmol) in 1,4-dioxane (10 mL) was stirred at 80°C under N₂ overnight, concentrated and purified by CC (PE/EA = 4/1) to give compound P65 (1.2 g, 80%) as a colorless solid. ¹H-NMR (400 MHz, CDCl₃) δ: 1.42 (s. 3H), 1.69 (s, 6H), 1.89 (br s, 1H), 7.45-7.50 (m, 2H), 7.82 (dd, J = 8.0, 1.6 Hz, 1H), 8.02 (d, J = 2.0 Hz, 1H), 8.18 (d, J = 2.0 Hz, 1H), 8.72 (d, J = 8.0 Hz, 1H).

A solution of 4-hydroxy-2-naphthoic acid (2.0 g, 10.8 mmol), t-BuNH₂ (1.5 g, 20.0 mmol), HATU (4.9 g, 13.0 mmol) and DIEA (1.4 g, 10.8 mmol) in DMF (10 mL) was stirred at 60°C for 1.5 h, cooled to rt, diluted with water and extracted with EA (3x). The combined organic layers were washed with water and brine, dried over Na₂SO₄, filtered, concentrated and purified by CC (PE/EA = 1/1) to give compound P66a (2.1 g, 81%) as a colorless solid. ¹H-NMR (400 MHz, CDCl₃) δ: 1.56 (s, 9H), 7.26 (br s, 1H), 7.62 (d, J = 1.6 Hz, 1H), 7.76-7.85 (m, 2H), 8.01 (d, J = 8.4 Hz, 1H), 8.15 (d, J = 8.4 Hz, 1H), 8.28 (s, 1H).

To a solution of compound P66a (3.80 g, 15.6 mmol) and TEA (4.73 g, 46.8 mmol) in DCM (20 mL) was added Tf₂O (6.60 g, 23.4 mmol) and the solution was stirred at rt for 2 h, diluted with DCM, washed with brine, dried over Na₂SO₄, filtered, concentrated and purified by CC (PE/EA = 4/1) to give compound P66b (5.0 g, 85%) as a colorless solid. ¹H-NMR (400 MHz, CDCl₃) δ: 1.55 (s, 9H), 7.23 (br s, 1H), 7.58 (d, J = 1.8 Hz, 1H), 7.66-7.75 (m, 2H), 8.00 (d, J = 8.2 Hz, 1H), 8.15 (d, J = 8.2 Hz, 1H).

Compound P66b (1.2 g, 3.2 mmol) was treated as described above in Example P65, Step 3 to give compound P66 (0.9 g, 80%) as a colorless solid. ¹H-NMR (400 MHz, CDCl₃) δ: 1.42 (s, 12H), 1.53 (s, 9H), 1.88 (br s, 1H), 7.45-7.50 (m, 2H), 7.82 (dd, J = 8.4 Hz, 1.6 Hz, 1H), 8.02 (d, J = 1.6 Hz, 1H), 8.18 (d, J =1.6 Hz, 1H), 8.72 (d, J = 8.4 Hz, 1H).

The mixture of 5-bromo-3-(trifluoromethyl)pyridin-2-ol (2.0 g, 8.26 mmol) and Lawesson's reagent (2.3 g, 5.79 mmol) in toluene (30 mL) was refluxed overnight, concentrated and purified by CC (PE/EA = 20/1) to give compound P67a (1.5 g, 70%) as a yellow solid.

The mixture of compound P67a (0.60 g, 2.33 mmol) and NCS (1.24 g, 9.30 mmol) in DCM (30 mL) was stirred at 15°C for 2.5 h, washed with water, dried over Na₂SO₄ and filtered. DIEA (0.60 g, 4.65 mmol) and tert-butylamine (0.20 g, 2.79 mmol) were added to the filtrate and the mixture was stirred at rt for 1 h, concentrated and purified by CC (PE/EA = 10/1) to give compound P67 (0.10 g, 12%) as a pale brown solid.

To a solution of 4-(tert-butyl)-2-methylphenol (10.6 g, 64.6 mmol) in dry CCl₄ (100 mL) was added Br₂ (10.9 g, 67.8 mmol) slowly and the solution was stirred at rt for 2 h, poured into sat. Na₂S₂O₃ and extracted with MTBE twice. The combined organic layers were washed with water and brine, dried over Na₂SO₄, filtered, concentrated and purified by CC (EA/PE = 1/100) to give compound P69a (15 g, 96%) as colorless oil.

To a solution of compound P69a (10.0 g, 41.1 mmol) in isopropanol (120 mL) was added aq. NaOH solution (20%, 120 mL) at -78°C, then CHClF₂ was bubbled into the solution and the solution was heated overnight at 40°C, cooled to rt, diluted with water and extracted with EA twice. The combined organic layers were washed with water and brine, dried over Na₂SO₄, filtered, concentrated and purified by CC (EA/PE = 1/50) to give compound P69b (5.1 g, 42%) as a colorless oil.

Compound P69b (4.8 g, 16.4 mmol) was treated as described above in Example P65, Step 3 to give compound P69 (3.2 g, 57%) as a colorless solid.

Compound P70 was prepared starting from 2-bromo-4,6-di-tert-butylphenol similar as described above in Example P69, Step 2 and 3.

To a solution of 2-methylpropane-2-sulfonamide (1.00 g, 7.30 mmol) in DMF (10 mL) was added NaH (60% w/t in mineral oil, 350 mg, 8.80 mmol) at 0°C and the solution was stirred for 30 min. Then a solution of 4-bromo-1-fluoro-2-(trifluoromethyl)benzene (1.80 g, 7.30 mmol) in DMF (10 mL) was added and the solution was stirred at 120°C overnight, cooled, diluted with H₂O and extracted with EA (3x 20 mL). The combined organic phases were dried over Na₂SO₄, filtered, concentrated and purified by CC (PE/EA = 8/1) to afford compound P71 (800 mg, 31%) as a colorless solid.

To a solution of 2-methylpropane-2-sulfonamide (173 mg, 1.15 mmol) in DMF (10 mL) was added NaH (60% w/t in mineral oil, 56 mg, 1.39 mmol) at 0°C and the solution was stirred for 30 min. Then a solution of 5-bromo-1,2-difluoro-3-(trifluoromethyl)benzene (300 mg, 1.15 mmol) in DMF (5 mL) was added and the solution was stirred at 120°C for 2 h, cooled, quenched with H₂O and extracted with EA (3x 20 mL). The combined organic phases were dried over Na₂SO₄, filtered, concentrated and purified by CC (PE/EA = 10/1) to afford compound P72 (130 mg, 31%) as a colorless solid.

A mixture of 5-nitro-6-(trifluoromethyl)pyridin-2(1H)-one (3.54 g, 17.0 mmol), DMF (4.96 g, 68 mmol) and POCl₃ (20.9 g, 136 mmol) was heated at 90°C for 16 h, evaporated, poured into ice-water (200 mL), neutralized to pH 5 with Na₂CO₃ and extracted with EA (3x 100 mL). The combined organic layers were dried over Na₂SO₄, filtered, concentrated and purified by CC (EA/PE = 1/20) to give compound P73a (2.77 g, 72%) as a yellow solid. ¹H-NMR (CDCl₃, 300 MHz) δ: 7.74 (1H, d, J = 8.4 Hz), 8.22 (1H, d, J = 8.4 Hz).

To a round bottom flask fitted with a centrally mounted stirrer, carrying a reflux condenser and a dropping funnel, was charged successively iron powder (2.18 g, 39 mmol) and ammonium chloride solution (65 mL, 1M, 65 mmol). A solution of compound P73a (2.95 g, 13 mmol) in MeOH (65 mL) was allowed to drop into the stirred slurry of iron powder-ammonium chloride solution over a duration of 10 min at rt. The mixture was stirred under reflux for 2h, filtrered hot followed by hot methanol wash (2x 30 mL) and the combined washings were concentrated to leave the product precipitating out from the solution. Recrystallization from MeOH/DCM gave compound P62b (2.0 g, 79%) as yellow solid. ¹H-NMR (CDCl₃, 300 MHz) δ: 4.27 (2H, br s), 7.09 (1H, d, J = 8.4 Hz), 7.25 (1H, d, J = 8.4 Hz).

Step (a): Thionyl chloride (42 mL) was added dropwise under ice cooling over 60 min to water (250 mL) maintaining the temperature of the mixture at 0-7°C. The solution was allowed to warm to 18°C and stirring was continued for 3 d. CuCl (151 mg) was added to the mixture and the resultant yellow-green solution was cooled to -3°C using an acetone/ice bath. Step (b): Hydrochloric acid (36% w/w, 12.2 mL) was added with agitation to compound P73b (1.65 g, 8.4 mmol), maintaining the temperature of the mixture below 30°C with ice cooling. The mixture was cooled to -5°C using an ice/acetone bath and a solution of sodium nitrite (0.68 g, 9.8 mmol) in water (2.8 mL) was added dropwise over 30 min maintaining the temperature of the mixture between -5 to 0°C. The resultant slurry was cooled to -2°C and stirred for 10 min. Step (c): The slurry from step (b) was cooled to -5°C and added to the solution obtained from step (a) over 95 min, maintaining the temperature of the mixture between -3 to 0°C (the slurry from step (b) was maintained at -5°C throughout the addition). As the reaction proceeded, a solid began to precipitate. When the addition was complete, the mixture was agitated at 0°C for 75 min. The solid was collected by vacuum filtration, washed with ice-cooled water (2x 25 mL) and dried under vacuum at below 25°C to give compound P73c (1.53 g, 66%) as yellow solid. ¹H-NMR (CDCl₃, 300 MHz) δ: 7.81 (1H, d, J = 8.4 Hz), 8.57 (1H, d, J = 8.4 Hz).

To a solution of 2-methylprop-2-ylamine (5 mL) in DCM (20 mL) was added a solution of compound P73c (1.53 g, 5.5 mmol) in DCM (10 mL) dropwise at 0°C and the solution was stirred at rt for 1 h, washed with water (3x 50 mL) and brine, dried over Na₂SO₄, filtered and concentrated to give compound P73d (1.2 g, 69%) as a yellow solid. ¹H-NMR (CDCl₃, 300 MHz) δ: 1.26 (9H, s), 4.87 (1H, s), 7.65 (1H, d, J = 8.4 Hz), 8.53 (1H, d, J = 8.4 Hz).

A solution of compound P73d (317 mg, 1.0 mmol), B₂Pin₂ (280 mg, 1.1 mmol), potassium acetate (294 mg, 3.0 mol) in 1,2-dimethoxyethane (5 mL) was sparged for 5 min with N₂ and then Pd(dppf)Cl₂ (82 mg, 0.1 mmol) was added. The mixture was heated under reflux for 12 h, diluted with EA (20 mL) and concentrated to dryness. The residue was taken up in EA (30 mL) and water (20 mL). The organic layer was washed with water (30 mL) and brine (30 mL), dried over Na₂SO₄, filtered, concentrated and re-crystallized from EA/PE = 1/8 to given compound P73 (200 mg, 46%) as a tan solid. ¹H-NMR (CDCl₃, 400 MHz) δ: 1.24 (9H, s), 1.40 (12H, s), 4.83 (1H, s), 8.11 (1H, d, J = 8.0 Hz), 8.54 (1H, d, J = 8.0 Hz).

NaOMe (5.4 g, 0.10 mol) was suspended in THF (100 mL) and treated at rt with ethyl formate (7.4 g, 0.10 mol) followed by dropwise addition of a solution 1-(4-hydroxy-2-(trifluoromethyl)phenyl)ethanone (16.3 g, 0.08 mol) in THF. The mixture was stirred for 2.5 h at rt, quenched with H₂O (300 mL) and extracted with Et₂O (100 mL). The extracts were discarded. The aqueous phase was acidified with 6M H₂SO₄ (18 mL) and extracted with Et₂O (2x 100 mL). This extract was washed with water and brine, dried over Na₂SO₄, filtered and concentrated to afford compound P74a (12.5 g, 67%) as a yellow solid.

A mixture of compound P74a (5.0 g, 22 mmol) and isopropylhydrazine hydrochloride (3.63 g, 33 mmol) in ethanol (80 mL) was stirred at 80°C for 2.5 h, concentrated and purified by CC (PE/EA = 10/1) to afford compound P74b (4.8 g, 81%) as a pale solid.

To a P74b (4.0 g, 14.8 mmol) in DCM (80 mL) was added TEA (3.0 g, 29.6 mmol) and Tf₂O (6.26 g, 22.2 mmol). The mixture was stirred at rt for 3.5 h and washed with water (30 mL). The organic phase was dried over Na₂SO₄, concentrated and purified by CC (PE/EA = 40/1) to afford product P74c (4.5 g, 76%) as a pale solid.

A mixture of P74c (2.0 g, 5.00 mmol), Pd(dppf)₂Cl₂ (0.2g, 0.25 mmol), B₂Pin₂ (1.9 g, 7.50 mmol) and KOAc (1.47g, 15.0 mmol) in 1,4-dioxane (200 mL) was stirred at 90°C under N₂ for 3 h, washed with water (400 mL) and extracted with EA (3x 100 mL). The combined organic phase was dried over Na₂SO₄ and evaporated to obtain product P74 (1.8 g, 95%).

To a solution of 2-(tert-butyl)-4-chlorophenol (30 g, 0.163 mol) and pyridine (21 mL, 0.26 mol) in dry DCM (500 mL) was added a solution of Tf₂O (33 ml, 0.19 mol) in dry DCM (150 mL) at 0°C and the solution was stirred for 4 h at rt, poured into 1M HCl and extracted with DCM. The organic layer was washed with brine, dried over Na₂SO₄, filtered, concentrated and purified by CC (PE/EA = 10/1) to give P75a (39 g, 87%) as a colorless liquid.

A solution of P75a (36 g, 0.13 mol), dppp (4.5 g, 11 mmol), Pd(OAc)₂ (2.4 g, 11 mmol) and NEt₃ (135 mL, 1.0 mol) in a mixture of MeOH (300 mL) and DMSO (400 mL) was stirred overnight at 55°C under an atmosphere of CO. Water and EA were added and the organic layer was separated, washed with water twice and brine, dried over Na₂SO₄, filtered, concentrated and purified by CC (PE/EA = 8/1) to give compound P75b (25.7 g, 89%) as a colorless solid.

To a solution of P75b (4.5 g, 20 mmol) in MeOH (30 mL) was added 3M NaOH (7 mL) and the mixture was refluxed for 12 h, concentrated and poured into water (50 mL), adjusted to pH 3 by adding 3M HCl and extracted with EA (3x 30 mL). The combined organic layers were dried over Na₂SO₄, filtered and concentrated to dryness to obtain crude product P75c (4.0 g, 95%).

A solution of P75c (2.1 g, 10 mmol), HATU (5.7 g, 15 mmol) and DIPEA (3.2 g, 25 mmol) in DMF (15 mL) was stirred at rt for 30 min. Then pivalohydrazide (1.7 g, 15 mmol) was added and the mixture was stirred for 12 h under rt, poured into H₂O (50 mL) and extracted with EA (3x 50 mL). The combined organic layer were dried over Na₂SO₄, filtered, concentrated and purified by prep. HPLC to afford compound P75d (2.5 g, 80%).

To a slurry of compound P75d (1.2 g, 3.8 mmol) in DCM (15 mL) was added pyridine (0.6 g, 7.6 mmol). The mixture was cooled to -10°C and Tf₂O (2.2 g, 7.6 mmol) was added dropwise. The mixture was stirred at -10°C for 1 h, at 0°C for 1 h and then warmed slowly to rt and stirred for 2 h, poured into H₂O (50 mL) and extracted with EA (3x 50 mL). The combined organic layers were dried over Na₂SO₄, filtered, concentrated and purified by CC to afford compound P75e (660 mg, 60%).

Compound P75e was treated as described above in Example P65, Step 3 to give compound P75 as a colorless solid.

A solution of 4-methoxy-3,3-dimethyl-4-oxobutanoic acid (180 mg, 1.12mmol) in SOCl₂ (6 mL) was stirred at rt for 2 h and concentrated. CuI (628 mg, 3.3 mmol) and Et₂O (8 mL) in a separate flask was treated with MeLi (22 mL, 3M) and the solution was stirred for 5 min. Then the resulting solution was cooled to -78°C. The acid chloride was added as a solution in Et₂O (1 mL) and the solution was stirred for additional 30 min, quenched by MeOH and warmed to rt over 2 h. Aq. NHCl₄ was added and the mixture was extracted with EA. The organic layer was concentrated to give compound P76a (60 mg, 33%) as a colorless oil.

To a solution of compound P76a (100 mg, 0.63 mmol) in DCM (10 mL) was added BnNH₂ (67 mg, 0.63 mmol), NaBH(AcO)₃ (186 mg, 0.88 mmol) and AcOH (0.04 mL) at 0°C. The mixture was allowed to reach rt and stirred overnight. Aq. NaOH (1 mL, 10%) was added dropwise and the mixture was extracted with DCM. The organic layer was concentrated and purified by CC (PE/EA = 5/1) to give compound P76b (40 mg, 30%) as a colorless oil.

Na (0.3 g, 13 mmol) was added to ammonia (10 mL) at -78°C, resulting in a dark blue solution. A solution of compound P76b (60 mg, 0.27 mmol) in THF (1 mL) was added and the solution was stirred at -40°C for 2 h, quenched with NHCl₄ and concentrated. The residue was diluted with water (5 mL) and extracted with EA. The organic layer was concentrated and purified CC (PE/EA = 2/1) to give compound P76c (30 mg, 87%) as a colorless solid.

A mixture of compound P76c (400 mg, 3.14 mmol) in conc. HCl (10 mL) was stirred at 120°C in a sealed tube for 48 h and concentrated. The obtained residue (300 mg, 1.63 mmol) was dissolved in MeOH (10 mL) and TMSCI (708 mg, 6.5 mmol) was added. The solution was stirred at rt for 24 h and concentrated to give compound P76 (350 mg, 57%) as an off-white solid.

2-Methyl-3-(trifluoromethyl)aniline (1.95 g, 11.1 mmol) was dissolved in (Ac)₂O (10 mL) and the mixture was stirred at rt overnight, partitioned between DCM (20 mL) and aq. NaHCO₃ (20 mL) and the aq. phase was extracted again with DCM (3x 20 mL). The combined organic layers were dried over Na₂SO₄, filtered, concentrated and purified by CC to afford compound P77a (2.08 g, 86%).

To a solution of compound P77a (2.08 g, 9.6 mmol) in HOAc (20 mL) was added under water-cooling a solution of bromine (1.8 mL) in HOAc (10 mL). The mixture was stirred at rt overnight and at 50°C for 2 h. Additional bromine (1.5 mL) was added under water-cooling and the mixture was stirred and heated to 50°C for 4 d, cooled to rt and poured into ice water. EA was added, followed by neutralization with K₂CO₃. The organic layer was separated, washed with aq. Na₂S₂O₃ and brine, dried over Na₂SO₄ and concentrated to afford compound P77b (388 mg, 16%).

To a solution of compound P77b (338 mg, 1.33 mmol) in EtOH (20 mL) was added 4M KOH (1 mL). The mixture was heated to reflux overnight, cooled to rt, concentrated, adjusted to pH∼4 with 4M HCl and extracted with EA. The organic layer was washed with brine and dried over Na₂SO₄, filtered, concentrated and purified by prep. HPLC to give compound P77c (186 mg, 56%) as colorless solid.

Compound P77 was prepared from P77c similar as described for compound P45.

Using similar procedures at that described in Preparative Example P77, the following compounds were prepared: # Structure # Structure P77/1 P77/2

To a solution of 1-tert-butyl 3-ethyl 3-aminoazetidine-1,3-dicarboxylate (366 mg, 1.50 mmol) in THF (10 mL) was added LiBH₄ (67 mg; 3 mmol) and the solution was refluxed for 20 min, quenched with H₂O, acidified with 2M aq. HCl, neutralized again with 2M aq. Na₂CO₃ and extracted with EA (3x). The combined organic layers were washed with water, dried over Na₂SO₄, filtered and concentrated to give compound P78a (300 mg, 99%) as a yellow oil.

To a solution of compound P78a (400 mg, 1.98 mmol) and NEt₃ (404 mg, 4.00 mmol) in DCM (10 mL) was added 2-chloroacetyl chloride (222 mg, 1.98 mmol) at 0°C and the solution was refluxed for 2 h, cooled to rt, washed with water and brine, dried over Na₂SO₄, filtered, concentrated and purified by CC (PE/EA =5/1) to give of compound P78b (145 mg, 30%) as a colourless oil.

A solution of compound P78b (145 mg, 0.60 mmol) and TFA (10 mL) was stirred for 6 h at rt and concentrated to give intermediate 78 (200 mg crude) as a TFA salt. ¹H-NMR (300 MHz, DMSO-d₆) δ: 3.98-3.95 (m, 1H), 4.12-4.08 (m, 5H), 4.53 (s, 2H), 8.54 (m, 3H). MS: 143 [M+1]⁺.

The solution of of 1-tert-butyl 3-ethyl 3-aminoazetidine-1,3-dicarboxylate (400 mg, 1.64 mmol), 2-[(tert-butoxy)carbonylamino] acetic acid (431 mg, 2.46 mmol), HOBT (332 mg, 2.46 mmol), EDCI (707 mg, 3.69 mmol) and DIEA (1 mL) in THF (20 mL) was stirred overnight at rt, washed with water and brine, dried over Na₂SO₄, filtered, concentrated and purified by CC (PE/EA = 2/1) to give compound P79a (500 mg, 76%) as a colorless solid.

A solution of compound P79a (500 mg, 1.25 mmol) and HCl in MeOH (3M, 10 mL) was stirred at rt for 1 h and then refluxed overnight, concentrated and diluted with Et₂O. The formed solid was collected by filtration, washed with Et₂O and dried in vacuum to give compound P79 (200 mg, 84%) as a mono HCl salt. ¹H-NMR (300 MHz, D₂O) δ: 4.69-4.65 (m, 2H), 4.51-4.47 (m, 2H), 4.19 (s, 2H). MS: 156 [M+1]⁺.

To a suspension of 2,2'-dichloroethyl ether (14.3 g, 100 mmol), K₂CO₃ (27.6 g, 200 mmol), KI (1.0 g, 6.00 mmol) in DMF (60 mL) was added methyl 3-oxobutanoate (13.9 g, 120 mmol) and the solution was stirred for 8 h at 80°C, diluted with water and extracted with EA (6x). The combined organic layers were dried over Na₂SO₄, filtered and the filtrate was distilled under reduced pressure (Kp 125 to 127°C, 1.3 kPa) to give compound P80a (8.0 g, 43%) as a pale yellow liquid.

A suspension of compound P80a (8.0 g, 43 mmol) and CuBr₂ (9.63 g, 43 mmol) in EA (100 mL) was stirred overnight at 40°C, filtered and the filtrate was concentrated and purified by CC (PE/EA = 20/1) to give compound P80b (2.0 g, 18%) as a colorless solid.

A solution of compound P80b (2.0 g, 7.5 mmol) in MeOH/NH₃ (10M, 100 mL) was stirred overnight at 50°C in a sealed tube, cooled to rt, concentrated and purified by CC (PE/EA = 8/1) to give compound P80c (800 mg, 63%) as a colorless solid.

A suspension of compound P80c (800 mg, 4.7 mmol), K₂CO₃ (1.19 g, 8.6 mmol) and NH₂OH·HCl (598 mg, 8.6 mmol) in EtOH (30 mL) was stirred for 6 h at rt and concentrated. EtOH (15 mL) and Raney-Ni (1 g) were added consecutively and the suspension was stirred under 50 psi of H₂ atmosphere for 3 h at 65°C, filtered and the filtrate was concentrated and purified by CC (PE/EA = 1/5) to give intermediate P80 (200 mg, 25%) as a colorless solid. ¹H-NMR (300 MHz, DMSO-d₆ + D₂O) δ: 3.87-3.81 (m, 1H), 3.75-3.69 (m, 1H), 3.59-3.48 (m, 2H), 3.42-3.36 (m, 1H), 3.29-3.26 (m, 1H), 2.86-2.81 (m, 1H), 1.58-1.43 (m, 4H). MS: 171 [M+1]⁺.

To a solution of tert-butyl (2-cyano-2-methylpropyl)carbamate (915 mg, 4.62 mmol) in DMF (25 mL) was added NaN₃ (450 mg, 6.93 mmol) and NH₄Cl (367 mg, 6.93 mmol). The reaction mixture was stirred at 110°C for 24 h, cooled, diluted with EA (20 mL) and washed with water (100 mL). The combined organic extracts were dried over Na₂SO₄, evaporated and purified by prep. HPLC to give compound P81a (345 mg, 31%) as a colorless solid.

A mixture of compound P81a (345 mg, 1.43 mmol) in HCl/MeOH (4M, 30 mL) was stirred at rt overnight and evaporated to give compound P81 (241 mg, 95%) as a colorless solid.

A mixture of tert-butyl (2-cyano-2-methylpropyl)carbamate (1.75 g, 8.85 mmol), NH₂OH·HCl (584 mg, 17.7 mmol) and EtONa (1.80 g, 26.6 mmol) in EtOH (50 mL) was stirred at 60°C overnight, poured into water and extracted with EA. The organic extracts were dried over Na₂SO₄ and evaporated to give compound P82a (1.53 g, 75%) as yellow oil.

A mixture of P82a (1.53 g, 6.64 mmol), dimethyl carbonate (1.32 g, 13.3 mmol), EtONa (903 mg, 13.3 mmol) in EtOH (50 mL) was stirred at 60°C overnight, poured into water and extracted with EA. The combined organic layers were dried and evaporated to afford compound P82b (700 mg, 41%) as yellow solid.

A mixture of compound P82b (700 mg, 2.73 mmol) in HCl/MeOH (4M, 30 mL) was stirred at rt overnight and evaporated to give compound P82 (420 mg, 98%) as a colorless solid.

A mixture of tert-butyl (2-cyanoethyl)carbamate (763 mg, 4.49 mmol), NH₂OH·HCl (296 mg, 8.98 mmol) and EtONa (916 mg, 13.5 mmol) in EtOH (50 mL) was stirred at 60°C overnight, poured into water and extracted with EA. The combined organic extracts were dried over Na₂SO₄ and evaporated to give compound P83a (775 mg, 85%) as yellow oil.

A mixture of compound P83a (772 mg, 3.80 mmol), 1,1'-carbonyldiimidazole (1.23 g, 7.61 mmol), EtONa (518 mg, 7.61 mmol) in EtOH (50 mL) was stirred at 60°C overnight, poured into water and extracted with EA. The combined organic layers were dried and evaporated to afford compound P83b (540 mg, 62%) as yellow solid.

A mixture of compound P83b (540 mg, 2.36 mmol) in HCl/MeOH (4M, 30 mL) was stirred at rt overnight and evaporated to give compound P83 (301 mg, 99%) as a colorless solid.

A mixture of 3-bromo-5-chlorobenzoic acid (2.3 g, 10 mmol), HATU (3.7 g, 10 mmol) and DIPEA (2 g, 15 mmol) in DMF (30 mL) was stirred at rt for 30 min. Then 2-methylbutan-2-amine (1.0 g, 10 mmol) was added and the mixture was stirred for 12 h under rt, poured into water (100 mL) and extracted with EA (3x 50 mL). The combined organic layer was dried over Na₂SO₄, filtered, evaporated and purified by CC to give compound P84a (2.3 g, 80%).

The mixture of compound P84a (2.0 g, 6.0 mmol), B₂Pin₂ (2.0 g, 8.5 mmol), KOAc (1.0 g, 10.5 mmol) and Pd(dppf)Cl₂ (100 mg) in 1,4-dioxane (50 mL) was stirred at 90°C under N₂ for 12 h, concentrated, poured into water (50 mL) and extracted with EA (3x 50 mL). The combined organic layer was dried over Na₂SO₄, filtered, evaporated and purified by CC to give compound P84 (1.1 g, 53%).

Compound P85 was prepared using similar procedures as described in WO2012/139775, Preparative Example P28, starting with 1,3-dibromo-5-chlorobenzene.

To a solution of 3-bromo-5-(trifluoromethoxy)benzoic acid (5.00 g, 17.5 mmol), N,O-dimethylhydroxylamine·HCl (4.20 g, 43.9 mmol), HATU (14.7 g, 38.7 mmol) in DMF (50 mL) was added TEA (9.8 mL, 70.2 mmol) in portions at 0°C and the solution was stirred overnight at rt, diluted with water and extracted with EA. The organic layer was washed with brine, dried over Na₂SO₄, filtered and concentrated to give compound P86a (5.5 g, 96%) as a yellow oil. ¹H-NMR (400 MHz, CDCl₃) δ: 3.37 (s, 3H), 3.56 (s, 3H), 7.48 (s, 1H), 7.52 (s, 1H), 7.80 (s, 1H).

To a solution of compound P86a (4.5 g, 13.7 mmol) in dry THF (50 mL) was added CH₃MgBr (3M in Et₂O, 9.2 mL, 27.6 mmol) in portions at -15°C and the solution was stirred for 15 min at this temperature and then at rt for 1 h, diluted with 1M HCl and extracted with EA. The organic layer was washed with brine, dried over Na₂SO₄, filtered and concentrated to give compound P86b (3.5 g, 90%) as a yellow oil. ¹H-NMR (400 MHz, CDCl₃) δ: 2.62 (s, 3H), 7.60 (s, 1H), 7.74 (s, 1H), 8.02 (m, 1H).

To a suspension of methyltriphenylphosphonium bromide (7.60 g, 21.2 mmol) in dry THF (150 mL) was added NaHMDS (1M in THF, 10.6 mL, 10.6 mmol) at -15°C and the solution was stirred further for 30 min. A solution of compound P86b (3.0 g, 10.6 mmol) in THF (5 mL) was added at -15°C and the mixture was stirred at rt for 1 h, diluted with water and extracted with EA. The organic layer was washed with brine, dried over Na₂SO₄, filtered, concentrated and purified by CC (PE) to give compound P86c (2.4 g, 81%) as a yellow oil. ¹H-NMR (400 MHz, CDCl₃) δ: 2.11 (d, J = 1.6 Hz, 3H), 5.19 (s, 1H), 5.38 (s, 1H), 7.22 (s, 1H), 7.29 (s, 1H), 7.52 (m, 1H).

To a suspension of Pd(OAc)₂ (1.0 g, 4.45 mmol) and compound P86c (3.0 g, 10.7 mmol) was added a solution of CH₂N₂ in Et₂O (1M, 20 mL, 20 mmol) at -10°C and the solution was stirred for 30 min, filtered and the filtrate was concentrated to give compound P86d (1.9 g, 60%) as a yellow oil. ¹H-NMR (400 MHz, CDCl₃) δ: 0.78-0.81 (m, 2H), 0.84-0.88 (m, 2H), 1.39 (s, 3H), 7.00 (s, 1H), 7.18 (s, 1H), 7.30 (m, 1H).

To a suspension of compound P86d (1.0 g, 3.4 mmol), KOAc (1.40 g, 13.8 mmol) and B₂Pin₂ (1.80 g, 7.08 mmol) in 1,4-dioxane (40 mL) was added Pd(dppf)Cl₂ (250 mg, 356 µmol) at rt under N₂ and the solution was heated overnight at 80°C, cooled to rt and filtered. The filtrate was concentrated and purified by CC (PE/EA = 50/1) to give compound P86 (1.0 g, 91%) as yellow oil. ¹H-NMR (300 MHz, CDCl₃) δ: 0.73-0.76 (m, 2H), 0.86-0.90 (m, 2H), 1.34 (s, 12H), 1.41 (s, 3H), 7.17 (s, 1H), 7.43 (s, 1H), 7.60 (s, 1H).

Compound P87 was prepared using similar procedures as described in Preparative Example P84.

A mixture of 2-(tert-butyl)aniline (1.0 g, 6.71 mmol), NaI (3.0 g, 20.1 mmol), K₂CO₃ (2.78 g, 20.1 mmol) and 2-chloro-N-(2-chloroethyl)-N-methylethanamine (1.04 g, 6.71 mmol) in diglyme (150 mL) was stirred at 170°C for 24 h, poured into water and extracted with EA. The organic layers were dried over Na₂SO₄, evaporated and purified by CC (DCM/MeOH = 19/1) to afford compound P89a (500 mg, 32%).

Compound P89a (200 mg, 0.86 mmol) and NaOAc (210 mg, 2.58 mmol) were dissolved in AcOH (5 mL) and the mixture was stirred at rt. Bromine (165 mg, 1.03 mmol) was added dropwise and the mixture was stirred for 2 h at rt, diluted with 2M NaOH (150 mL) and extracted with EA. The combined organic phases were dried over Na₂SO₄, filtered, concentrated and purified by prep. HPLC to afford compound P89b (40 mg, 15%).

This compound was prepared using a similar procedure as described in Preparative Example P86, Step 5.

A mixture of 1-(3-bromo-5-(trifluoromethyl)phenyl)ethanone (0.5 g, 1.8 mmol) in THF (10 mL) was cooled to 0°C and treated dropwise with MeMgBr (1M in Et₂O, 10 mmol, 10 mL). Upon completion of addition, the resulting suspension was allowed to warm to rt and was stirred for 5 h, slowly diluted with saturated aq. NH₄Cl (10 mL) and EA (10 mL). The layers were separated and the aq. layer was extracted with EA (3x 30 mL). The combined organic layers were dried over MgSO₄, evaporated and purified by CC to afford compound P90a (0.47 g, 93%).

Compound P90 was prepared using a similar procedure as described in Preparative Example P86, Step 5.

To a mixture of pivalimidamide (586 mg, 5.86 mmol) and ethyl 4,4-dimethyl-3-oxopentanoate (1.21 g, 7.03 mmol) in MeOH (30 mL) was added NaOMe (623 mg, 11.7 mmol) under Ar. The mixture was refluxed at 75°C overnight, diluted with water (20 mL) and extracted with EA (3x 20 mL). The organic layer was washed with brine, dried over Na₂SO₄ and concentrated to give compound P91a (1.04 g, 85%) as colorless solid.

Compound P91a (1.04 g, 4.99 mmol) and POBr₃ (10 g) was stirred at 65°C for 1 h, poured into ice/water and extracted with EA. The organic layer was dried over MgSO₄, filtered and concentrated to give compound P91 (1.20 g, 89%) as a yellow oil.

NH₄Cl (129 mg, 2.43 mmol) was suspended in toluene (10 mL) and the slurry cooled to 0°C. AlMe₃ (2M in toluene, 2.43 mmol) was added at 0°C and the mixture was allowed to warm to rt and stirred until gas evolution had ceased. Methyl 1-methylcyclopropanecarboxylate (114 mg, 1.62 mmol) was added and the mixture stirred at 80°C overnight, cooled to rt, diluted with MeOH and stirred at rt for 1 h. The solution was filtered, the solids washed with MeOH and the solvent was removed in vacuo to afford the compound P92a (100 mg, 63%).

To a mixture of compound P92a (63 mg, 0.64 mmol) and methyl 4,4-dimethyl-3-oxopentanoate (121 mg, 0.77 mmol) in MeOH (30 mL) was added NaOMe (86 mg, 1.61 mmol) under Ar. The mixture was refluxed at 75°C overnight, diluted with water (20 mL) and extracted with EA (3x 20 mL). The combined organic layer was washed with brine, dried over Na₂SO₄ and concentrated to give compound P92b (112 mg, 85%) as a colorless solid.

Compound P92b (105 mg, 0.51 mmol) and POBr₃ (200 mg) was stirred without solvent at 65°C for 1 h, poured into ice/water and extracted with EA. The organic layer was dried over MgSO₄, filtered and concentrated to give compound P92 (121 mg, 89%) as yellow oil.

To a solution of 1-(1-methylcyclopropyl)ethanone (328 mg, 3.35 mmol) in THF (90 mL) was added LiHMDS (1M in THF, 2.5 mL) at -78°C. The cooling bath was removed and the mixture was stirred at rt for 30 min. Dimethyl carbonate (452 mg, 5.03 mmol) was added and the mixture stirred at rt overnight, evaporated, diluted with water and EA, acidified with AcOH and extracted with EA. The organic layer was dried over MgSO₄, filtered, concentrated and purified by CC (EA/PE = 1/9) to give compound P93a (68 mg, 13%) as a yellow oil.

To a mixture of compound P93a (60 mg, 0.38 mmol) and pivalimidamide (46 mg, 0.46 mmol) in MeOH (30 mL) was added NaOMe (51 mg, 0.95 mmol) under Ar. The mixture was refluxed at 75°C overnight, diluted with water (20 mL) and extracted with EA (3x 20 mL). The organic layer was washed with brine, dried over Na₂SO₄ and concentrated to give compound P93b (63 mg, 80%) as a colorless solid.

To a mixture of compound P93b (57 mg, 0.28 mmol) in DCM (10 mL) was added Tf₂O (118 mg, 0.42 mmol) and TEA (71 mg, 0.70 mmol) and the mixture was stirred at rt overnight, poured into water and extracted with DCM. The organic layer was dried over MgSO₄, filtered and concentrated to afford compound P93 (81 mg, 86%) as a yellow oil.

To a solution of dimethyl 5-bromoisophthalate (5.0 g, 18.3 mmol) in a mixture of THF (25 mL) and MeOH (25 mL) was added NaOH (740 mg, 18.4 mmol) and the mixture was stirred at rt overnight, concentrated, diluted with 2M HCl (20 mL) and extracted with EA. The combined organic layers were dried over MgSO₄, filtered and concentrated. The crude product was washed with a mixture of PE/EA (10:1, 10 mL) to give compound P94a (4.2 g, 88%) as a colorless solid.

A solution of compound P94a (400 mg, 1.54 mmol) in SOCl₂ (10 mL) was heated at reflux for 2 h, concentrated and coevaporated with toluene twice. The residue was dissolved in dry DCM (6 mL). TEA (0.2 mL) and tert-butylamine (0.15 mL) were added and the solution was stirred for further 40 min, concentrated and purified by CC (PE/EA = 10:1) to give compound P94b (360 mg, 76%) as a colorless oil.

A flask was charged with compound P94b (360 mg, 1.15 mmol), B₂Pin₂ (1.57 g, 5.4 mmol), KOAc (0.72 g, 7.3 mmol), Pd(dppf)Cl₂ (60 mg) and DMF (10 mL) and the mixture was stirred at 90°C for 12 h, cooled, concentrated and purified by CC (PE/EA = 10/1) to give compound P94 (315 mg, 76%) as a colorless solid.

A solution of compound P94a (3.8 g, 14.7 mmol) in SOCl₂ (40 mL) was heated at reflux for 2 h, concentrated and diluted with dry DCM (200 mL). Then the solution was added to a stirring solution of N,O-dimethylhydroxylamine hydrochloride (1.69 g, 17.6 mmol) and NEt₃ (6 mL) in dry DCM (60 mL) slowly at 0°C and the solution was stirred for 1 h at rt, poured into water. The organic layer was separated, washed with water and brine, dried over Na₂SO₄, filtered and concentrated to give crude compound P95a (4.2 g, 94%) as a light brown oil.

To a solution of compound P95a (4.2 g, 14.0 mmol) in dry THF (120 mL) was added MeMgBr (3M in Et₂O, 5.5 mL, 16.7 mmol) dropwise at 0°C and the solution was stirred for 4 h at rt, quenched with aq. NHCl₄ and extracted with EA twice. The combined organic layers were washed with water and brine consecutively, dried over Na₂SO₄, filtered and concentrated to give crude compound P95b (2.5 g) which contains 15% compound P95c (based on LCMS) as a colorless oil

To a solution of crude compound P95b (2.5 g, 9.7 mmol) in dry THF (50 mL) was added MeMgBr (3M in Et₂O, 3.7 mL, 11.1 mmol) dropwise at 0°C and the solution was stirred for 4 h at rt, quenched with aq. NHCl₄ and extracted with EA twice. The combined organic layers were washed with water and brine consecutively, dried over Na₂SO₄, filtered and concentrated to give crude compound P95c (2.1 g, 79% over two steps) as pale yellow oil.

A flask was charged with compound P95c (900 mg, 3.3 mmol), B₂Pin₂ (4.5 g, 17.8 mmol), KOAc (2.3 g, 23.1 mmol), Pd(dppf)Cl₂ (100 mg) and DMF (200 mL) and the solution was stirred at 100°C for 12 h, concentrated and purified by CC (PE/EA = 10/1) to give compound P95 (650 mg, 62%) as a colorless solid.

To a solution of compound P95c (1.1 g, 4.0 mmol) in dry THF (20 mL) was added NaH (195 mg, 8.0 mmol) under N₂ and the suspension was stirred for 1 h at rt. Then MeI (1.72 g, 12.0 mmol) was added and the solution was stirred at 70°C in a sealed tube overnight, poured into water and extracted with Et₂O. The organic layer was washed with water and brine, dried over Na₂SO₄, filtered, concentrated and purified by CC (PE) to give compound P96a (600 mg, 52%) as a colorless oil.

A flask was charged with compound P96a (600 mg, 2.1 mmol), B₂Pin₂ (1.07 g, 4.2 mmol), KOAc (1.44 g, 14.7 mmol), Pd(dppf)Cl₂ (60 mg) and DMF (10 mL) and the solution was stirred at 100°C for 12 h, cooled, concentrated and purified by CC (PE/EA = 20/1) to give compound P96 (400 mg, 57%) as a colorless solid.

To a solution of 2-(spiro[chroman-4,1'-cyclopropan]-8-yl)propan-2-ol (prepared as described in WO2012/139775, Preparative Example P39) (1.0 g, 4.58 mmol) in dry THF (10 mL) was added NBS (980 mg, 5.5 mmol) and the mixture was heated at reflux overnight, cooled, poured into water and extracted with EA twice. The combined organic layers were washed with brine, dried over Na₂SO₄, filtered, concentrated and purified by CC (PE/EA = 100/1) to give 2-(6-bromospiro[chroman-4,1'-cyclopropan]-8-yl)propan-2-ol (180 mg, 14%) and compound P97a (300 mg, 24%) as a colorless oil.

A mixture of compound P97a (300 mg, 1.08 mmol), Pin₂B₂ (386 mg, 1.52 mmol), Pd(dppf)Cl₂ (30 mg) and KOAc (150 mg, 1.52 mmol) in DMF (5 mL) under N₂ atmosphere was stirred at 95°C overnight, concentrated and purified by CC (PE/EA = 10/1) to give compound P97 (128 mg, 36%) as a colorless solid.

A solution of 1-cyclohexylethanol (1.28 g, 10 mmol) in DCM (50 mL), mesylchloride (15 mmol), Et₃N (30 mmol) was added under 0°C. The mixture was stirred for additional 2 h, quenched with ice water and extracted with EA. The organic layer was separated, washed with brine and dried over Na₂SO₄. After filtration, the filtrate was evaporated and the crude intermediate 1a was used in the next step.

Under N₂, vinyl acetate (86 g, 1.0 mol) was dissolved in dry CCl₄ (200 mL) and bromine (160 g, 1 mol) in dry CCl₄ (100 mL) was added dropwise over 2 h with vigorous stirring in an ice-water bath below 10°C. The mixture was stirred for additional 30 min and solvent was removed to give crude product 1b, which was used for the next step without further purification.

NH₃ (gas) was bubbled to a stirred solution of compound 1b (24.6 g, 10 mmol) and ethyl 3-oxobutanoate (13.0 g, 0.1 mol) in dry THF for 15 min. The solid was filtered off and solvent was removed to give crude product 1c.

To a solution of compound 1c (1.53 g, 10 mmol) in dry DMF (10 mL) was added NaH (60% in mineral oil, 1.2 g, 0.03 mol) in an ice-water bath below 0°C. The mixture was stirred for 30 min and then compound 1a (3.09 g, 15 mmol) was added to the mixture. The mixture was stirred for additional 12 h, quenched with ice water and extracted with EA. The organic layer was separated and washed with brine and dried over Na₂SO₄. After filtration, the filtrate was evaporated and purified by CC (EA/PE = 1/60) to give compound 1d (1.63 g, 62%) as a pale yellow oil.

To a solution of compound 1d (1.32 g, 5.0 mmol) in dry THF (25mL) was added NBS (0.89 g, 5 mmol) at -78°C under N₂. The reaction was stirred 5 min (monitored by TLC) and quenched with cold aq. NH₄Cl. The organic layer was separated and the aq. layer extracted repeatedly with EA. The combined organic layer was washed with brine and dried over Na₂SO₄. After filtration, the filtrate was evaporated and purified by CC (EA/PE= 1/60) to give compound 1e (1.57 g, 92%).

A suspension of compound 1e (1.71 g, 5 mmol), Cs₂CO₃ (3.25 g 10 mmol), 2-(3,5-di-tert-butylphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (2.37 g, 7.5 mmol), Pd(dppf)Cl₂ (30 mg) in 1,4-dioxane/H₂O(10:1, 50 mL) was heated overnight under N₂ at 90°C. After cooling, the mixture was concentrated and extracted with EA. The organic layer was washed with brine, dried over magnesium sulfate, filtered, concentrated and purified by CC (EA/PE = 1/50) to give compound 1f (903 mg, 40%).

To a solution of compound 1f (902 mg, 2 mmol) in EtOH (20 mL) was added 5M KOH (10 mL). The mixture was refluxed overnight, the solvent was removed under reduced pressure and the residue was adjusted to pH<2 with 4M HCl. The mixture was extracted with EA three times and the combined organic layer was washed with brine and dried over Na₂SO₄. After filtration, the filtrate was evaporated and purified by prep. HPLC to give pure product 1g as a colorless solid.

To a solution of compound 1g (85 mg, 0.2 mmol) in DMF (5 mL) was added HATU (152 mg, 0.4 mmol) and DIPEA (129 mg, 1 mmol). The mixture was stirred for 60 min and then oxetan-3-amine (110 mg, 1.5 mmol) was added to the mixture. The mixture was stirred overnight and quenched with ice water and extracted with EA. The organic layer was separated washed with brine and dried over Na₂SO₄. After filtration, the filtrate was evaporated and purified by prep. HPLC to give compound 1 (40 mg, 42%) as a colorless solid. ¹H-NMR (500 MHz, DMSO-d₆) δ: 0.63 (m, 2H), 1.01 (m, 4H), 1.13-1.31 (m, 20H), 1.47 (m, 6H), 2.57 (s, 3H), 3.86 (m, 1H), 4.52 (m, 2H), 4.70 (m, 2H), 4.95 (m, 1H), 6.50 (s, 1H), 7.09 (s, 2H), 7.39 (s, 1H), 8.19 (d, 1H). MS: 479.4 (M+1).

The following Examples were prepared similar as in Example 1: # Structure Analytical data 1/1 ¹H-NMR (400 MHz, DMSO-d₆) δ: 7.88 (t, J = 5.6 Hz, 1H), 7.36 (s, 1H), 7.15 (d, J = 1.6 Hz, 1H), 6.46 (s, 1H), 3.77 (d, J = 7.2 Hz, 2H), 3.60-3.55 (m, 2H), 3.31 (t, J = 7.0 Hz, 2H), 3.01 (s, 3H), 2.53 (s, 3H), 1.46-1.43 (m, 3H), 1.31-1.21 (m, 21H), 0.93-0.88 (m, 3H), 0.68-0.62 (m, 2H). MS: 515.1 (M+1). 1/2 ¹H-NMR (400 MHz, DMSO-d₆) δ: 7.80 (t, J = 6.0 Hz, 1H), 7.36 (t, J = 1.8 Hz, 1H), 7.16 (d, J = 1.6 Hz, 2H), 6.53 (s, 1H), 4.47 (d, J = 5.6 Hz, 2H), 4.15 (d, J = 5.6 Hz, 2H), 3.76 (d, J = 7.2 Hz, 2H), 3.34 (d, J = 6.0 Hz, 2H), 2.52 (s, 3H), 1.46-1.44 (m, 3H), 1.34-1.23 (m, 24H), 0.95-0.89 (m, 3H), 0.66-0.60 (m, 2H). MS: 493.4 (M+1). 1/3 ¹H-NMR (400 MHz, DMSO-d₆) δ: 7.36-7.31 (m, 2H), 7.20 (s, 1H), 7.15 (d, J = 1.6 Hz, 2H), 6.84 (s, 1H), 6.42 (s, 1H), 3.75 (d, J = 7.2 Hz, 2H), 3.29 (s, 2H), 2.51 (s, 3H), 1.46-1.43 (m, 3H), 1.31-1.22 (m, 21H), 1.07 (s, 6H), 0.95-0.89 (m, 3H), 0.67-0.60 (m, 2H). MS: 508.2 (M+1). 1/4 ¹H-NMR (400 MHz, DMSO-d₆) δ: 7.65 (t, J = 6.2 Hz, 1H), 7.36 (s, 1H), 7.16 (d, J = 1.6 Hz, 2H), 7.04 (s, 1H), 6.50 (s, 1H), 3.76 (d, J = 7.2 Hz, 2H), 3.28 (d, J = 6.4 Hz, 2H), 2.95 (s, 3H), 2.52 (s, 3H), 1.46-1.43 (m, 3H), 1.31-1.15 (m, 27H), 0.95-0.87 (m, 3H), 0.68-0.59 (m, 2H). MS: 558.1 (M+1). 1/5 ¹H-NMR (400 MHz, DMSO-d₆) δ: 7.81 (t, J = 5.8 Hz, 1H), 7.36 (s, 1H), 7.22 (s, 1H), 7.17 (d, J = 1.6 Hz, 1H), 6.96 (s, 1H), 6.53 (s, 1H), 3.78 (d, J = 7.2 Hz, 2H), 3.72 (d, J = 5.6 Hz, 2H), 2.53 (s, 3H), 1.46-1.43 (m, 3H), 1.31-1.15 (m, 21H), 0.93-0.86 (m, 3H), 0.69-0.61 (m, 2H). MS: 466.1 (M+1). 1/6 ¹H-NMR (400 MHz, DMSO-d₆) δ: 7.65 (t, 1H), 7.36 (s, 1H), 7.17 (d, J = 1.6 Hz, 2H), 6.51 (s, 1H), 3.99 (d, J = 5.2 Hz, 2H), 3.77 (d, J = 7.2 Hz, 2H), 3.00 (s, 3H), 2.84 (s, 3H), 2.52 (s, 3H), 1.46-1.43 (m, 3H), 1.35-1.23 (m, 21H), 0.94-0.85 (m, 3H), 0.67-0.61 (m, 2H). MS: 494.2 (M+1). 1/7 ¹H-NMR (400 MHz, DMSO-d₆) δ: 7.35 (t, J = 2.0 Hz, 1H), 7.15 (d, J = 2.0 Hz, 2H), 6.18 (s, 1H), 4.47-3.68 (m, 8H), 2.46 (s, 3H), 1.46-1.43 (m, 3H), 1.31-1.21 (m, 21H), 0.98-0.85 (m, 3H), 0.68-0.60 (m, 2H). MS: 465.1 (M+1). 1/8 ¹H-NMR (400 MHz, DMSO-d₆) δ: 7.36 (t, J = 1.6 Hz, 1H), 7.15 (d, J = 1.6 Hz, 2H), 6.21 (s, 1H), 4.43-3.69 (m, 7H), 3.21 (s, 3H), 2.47 (s, 3H), 1.46-1.35 (m, 3H), 1.31-1.15 (m, 21H), 1.00-0.85 (m, 3H), 0.68-0.60 (m, 2H). MS: 479.1 (M+1). 1/9 ¹H-NMR (400 MHz, DMSO-d₆) δ: 7.80 (t= J = 5.8 J = 5.8 Hz, 1H), 7.36 (s, 1H), 7.15 (d, J = 1.6 Hz, 2H), 6.92 (s, 2H), 6.44 (s, 1H), 3.76 (d, J = 7.2 Hz, 2H), 3.56 (q, 2H), 3.18 (t, J = 7.4 Hz, 2H), 2.53 (s, 3H), 1.46-1.43 (m, 3H), 1.31-1.21 (m, 21H), 0.94-0.88 (m, 3H), 0.68-0.60 (m, 2H). MS: 516.1 (M+1). 1/10 ¹H-NMR (400 MHz, CDCl₃) δ: 8.18 (d, J = 8.4 Hz, 1H), 7.59 (s, 1H), 7.26 (d, J = 8.4 Hz, 1H), 6.26 (s, 1H), 5.89 (m, 1H), 4.56 (s, 1H), 4.00 (m, 2H), 3.77 (d, J = 7.2 Hz, 2H), 3.38 (m, 2H), 3.30 (m, 2H), 2.63 (s, 3H), 1.86 (m, 1H), 1.66 (m, 11H), 1.55-1.51 (m, 3H), 1.42-1.24 (m, 14H), 1.01-0.92 (m, 3H), 0.60 (m, 2H). MS: 586.1 (M+1)⁺. 1/11 ¹H-NMR (400 MHz, DMSO-d₆) δ: 8.12 (d, J = 8.4 Hz, 1H), 7.74 (s, 1H), 7.63 (m, 1H), 7.52 (s, 1H), 7.40 (m, 1H), 6.62 (s, 1H), 3.84 (m, 2H), 3.56 (m, 4H), 3.27 (m, 2H), 2.52 (s, 3H), 2.38 (m, 6H), 1.54 (s, 9H), 1.43 (m, 3H), 1.22-1.12 (m, 12H), 0.99-0.82 (m, 3H), 0.59 (m, 2H). MS: 601.1 (M+1)⁺. 1/12 ¹H-NMR (400 MHz, DMSO-d₆) δ: 8.45 (s, 1H), 7.36 (t, J = 1.6 Hz, 1H), 7.15 (d, J = 1.6 Hz, 2H), 6.48 (s, 1H), 3.77 (d, J = 6.8 Hz, 2H), 2.54 (s, 3H), 1.50-1.43 (m, 5H), 1.30-1.14 (m, 22H), 0.94-0.86 (m, 3H), 0.67-0.60 (m, 2H). MS: 474.1 (M+1). 1/13 ¹H-NMR (400 MHz, CDCl₃) δ: 8.21 (d, J = 8.4 Hz, 1H), 7.59 (s, 1H), 7.27 (d, J = 8.4 Hz, 1H), 6.31 (s, 1H), 5.52 (br s, 2H), 4.67 (s, 1H), 3.80 (d, J = 6.8 Hz, 2H), 2.63 (s, 3H), 1.62 (s, 9H), 1.53 (m, 3H), 1.35-1.29 (m, 12H), 1.02-0.95 (m, 3H), 0.61 (m, 2H). MS Found: 488.5 (M+1)⁺. 1/14 ¹H-NMR (400 MHz, DMSO-d₆) δ: 8.19 (d, J = 8.0 Hz, 1H), 7.36(s,1H), 7.16(d, J = 1.6Hz, Hz, 1H), 7.36 (s, 1H), 7.16 (d, J = 1.6 Hz, 2H), 6.53 (s, 1H), 5.22-5.16 (m, 1H), 3.76 (d, J = 6.8 Hz, 2H), 3.50 (t, J = 9.0 Hz, 2H), 3.19 (t, J = 10.4 Hz, 2H), 2.43 (s, 3H), 1.45-1.40 (m, 3H), 1.31-1.15 (m, 21H), 0.97-0.87 (m, 3H), 0.67-0.58 (m, 2H). MS: 481.1 (M+1). 1/15 ¹H-NMR (400 MHz, DMSO-d₆) δ: 8.12 (d, J = 7.2 Hz, 1H), 7.36 (t, J = 1.6 Hz, 1H), 7.16 (d, J = 1.6 Hz, 2H), 6.56 (s, 1H), 4.63-4.58 (m, 1H), 4.06-4.02 (m, 2H), 3.81-3.76 (m, 4H), 2.51 (s, 3H), 1.45-1.43 (m, 3H), 1.38 (s, 9H), 1.31 (s, 18H), 1.27-1.15 (m, 3H), 0.92-0.84 (m, 3H), 0.67-0.59 (m, 2H). MS: 564.2 (M+1). 1/16 ¹H-NMR (300 MHz, CDCl₃) δ: 0.66-0.72 (m, 2H), 0.97-1.04 (m, 9H), 1.25-1.43 (m, 4H), 1.58-1.63 (m, 4H), 2.60 (s, 3H), 3.85 (d, J = 7.2 Hz, 2H), 4.07 (s, 2H), 4.57 (t, J = 6.6 Hz, 2H), 4.98 (t, J = 7.2 Hz, 2H), 5.15-5.23 (m, 1H), 6.23-6.25 (m, 1H), 6.45 (s, 1H), 6.86 (s, 1H), 7.21 (s, 1H). MS: 508 (M+1)⁺. 1/17 ¹H-NMR (300 MHz, CDCl₃) δ: 0.66-0.72 (m, 2H), 0.98-1.06 (m, 3H), 1.23-1.40 (m, 12H), 1.51-1.58 (m, 3H), 2.59 (s, 3H), 3.83 (d, J = 7.2 Hz, 2H), 4.57 (t, J = 6.6 Hz, 2H), 4.82 (q, J = 8.7 Hz, 2H), 4.99 (t, J = 7.2 Hz, 2H), 5.15-5.23 (m, 1H), 6.19 (d, J = 7.2 Hz, 2H), 6.35 (s, 1H), 6.62 (d, J = 0.9 Hz, 1H), 6.93 (d, J = 0.9 Hz, 1H). MS: 508 (M+1)⁺. 1/18 ¹H-NMR (400 MHz, DMSO-d₆) δ: 8.23-8.20 m (2H), 7.18 (s, 1 H), 7.17 (s, 1H), 6.57 (s, 1H), 4.97-4.92 (m, 1H), 4.71 (t, 2H), 4.54 (t, 2H), 3.75 (d, 2H), 2.42 (s, 3H), 1.48-1.46 (m, 3H), 1.41 (s, 9H), 1.36-1.24 (m, 9H), 0.97-0.92 (m, 3H), 0.73-0.64 (m, 2H). MS: 506.3 (M+1). 1/19 ¹H-NMR (400 MHz, CDCl₃) δ: 7.32 (d, 1H), 7.04 (d, 1H), 6.23 (s, 1H), 6.20 (d, J = 7.2 Hz, 2H), 5.23-5.20 (m, 1H), 5.00 (t, 2H), 4.57 (t, 2H), 3.74 (d, J = 6.8 Hz, 2H), 3.29 (s, 3H), 2.60 (s, 3H), 2.50 (br s, 2H), 1.56-1.54 (m, 3H), 1.45 (s, 9H), 1.42-1.18 (m, 9H), 1.02-1.00 (d, 3H), 0.69-0.65 (m, 2H). MS: 520.3 (M+1). 1/20 n.d. 1/21 n.d. 1/22 ¹H-NMR (300 MHz, DMSO-d₆) δ: 8.31 (d, J = 6.6 Hz, 1H), 7.58 (s, 1H), 7.46 (s, 1H), 6.78 (s, 1H), 4.98-4.92 (m, 1H), 4.73 (t, J = 6.8 Hz, 2H), 4.55 (t, J = 6.2 Hz, 2H), 3.94-3.84 (m, 3H), 3.58-3.51 (m, 1H), 2.53 (s, 3H), 1.54-1.44 (m, 15H), 1.31-1.20(m, 9H), 0.95-0.88 (m, 3H), 0.70-0.62 (m, 2H). MS: 556.4 (M+1). 1/23 n.d. 1/24 ¹H-NMR (400 MHz, CDCl₃,) δ: 7.26 (s, 1H), 7.22 (d, 1H, J = 2.0 Hz), 7.10 (t, 1H, J = 2.0 Hz), 6.16 (s, 1H), 6.15 (s, 1H), 5.28 (s, 2H), 5.18-5.23 (m, 1H), 4.98 (t, 2H, J = 9.6 Hz), 4.57 (t, 2H, J = 8.8 Hz), 3.70 (d, 2H, J = 7.2 Hz), 3.54 (s, 3H), 2.60 (s, 3H), 1.55-1.51 (m, 3H), 1.45-1.31 (m, 12H), 1.03-0.97 (m, 3H), 0.68-0.64 (m, 2H). MS: 469 (M+1). 1/25 n.d. 1/26 ¹H-NMR (500 MHz, CDCl₃) δ: 8.14 (d, J = 8.5 Hz, 1H), 7.71 (d, J = 2.0 Hz, 1H), 7.36 (dd, J = 8.5, 2.0 Hz, 1H), 6.44 (s, 1H), 6.89 (s, 1H), 6.02 (t, J = 6.0 Hz, 1H), 4.53 (s, 1H), 3.86 (d, J = 7.5 Hz, 2H), 3.34 (d, J = 6.0 Hz, 2H), 1.71 (m, 6H), 1.61 (s, 9H), 1.31 (s, 9H), 1.26 (m, 3H), 1.17 (s, 6H), 0.97 (m, 2H). MS: 614.2 (M+1). 1/27 ¹H-NMR (500 MHz, CDCl₃) δ: 8.13 (d, J = 8.0 Hz, 1H), 7.68 (d, J = 2.0 Hz, 1H), 7.35 (dd, J = 8.0, 2.0 Hz, 1H), 6.89 (s, 1H), 6.89 (s, 1H), 5.97 (t, J = 6.0 Hz, 1H), 4.46 (s, 1H), 3.87 (d, J = 7.5 Hz, 2H), 3.74 (dd, J = 7.5, 3.0 Hz, 4H), 3.38 (d, J = 6.0 Hz, 2H), 1.78 (m, 5H), 1.60 (s, 9H), 1.57 (m, 4H), 1.47 (m, 2H), 1.33 (s, 9H), 1.29 (m, 4H), 1.00 (m, 2H). MS: 656.2 (M+1). 1/28 ¹H-NMR (500 MHz, CDCl₃) δ: 8.21 (d, J = 8.0 Hz, 1H), 7.63 (d, J = 2.0 Hz, 1H), 7.29 (dd, J = 8.0, 2.0 Hz, 1H), 6.88 (s, 1H), 6.49 (s, 1H), 4.80 (s, 2H), 4.63 (s, 1H), 3.92 (d, J = 6.0 Hz, 2H), 3.46 (m, 5H), 1.62 (s, 9H), 1.56 (m, 3H), 1.29 (m, 21H), 0.98 (m, 3H), 0.65 (m, 2H). MS: 558.3 (M-OCH₃)⁺. 1/29 ¹H-NMR (500 MHz, CDCl₃) δ: 8.21 (d, J = 8.0 Hz, 1H), 7.62 (d, J = 2.0 Hz, 1H), 7.29 (d, 2.0 Hz, 1H), 6.53 (d, J = 8.0, 1H), 6.49 (s, 1H), 4.72 (s, 3H), 4.19 (m, 1H), 4.00 (m, 2H), 3.90 (d, J = 6.0 Hz, 2H), 3.57 (t, J = 6.0 Hz, 2H), 2.03 (d, J = 12.5 Hz, 2H), 1.75 (s, 2H), 1.62 (s, 9H), 1.58 (m, 5H), 1.30 (m, 13H), 0.99 (m, 3H), 0.64 (m, 2H). MS: 570.3 (M-OCH₃)⁺. 1/30 ¹H-NMR (CDCl₃, 300 MHz) δ: 7.40 (d, 1H, J = 1.5 Hz), 7.25 (d, 1H, J = 7.5 Hz), 7.13 (dd, 1H, J = 7.5 Hz, 1.5 Hz), 6.19-6.16 (m, 2H), 5.57 (s, 1H), 5.22-5.17 (m, 1H), 4.99 (t, 2H, J = 6.6 Hz), 4.58 (t, 2H, J = 6.6 Hz), 3.75 (d, 2H, J = 7.2 Hz), 2.59 (s, 3H), 1.55-1.51 (m, 3H), 1.50-1.47 (m, 18H), 1.43-1.33 (m, 3H), 1.02-0.93 (m, 12H), 0.68-0.64 (m, 2H). MS: 508 (M+1) 1/31 ¹H-NMR (CDCl₃, 400 MHz) δ: 7.40 (d, 1H, J = 2.4 Hz), 7.14 (dd, 1H, J = 10.0 Hz, 2.0 Hz), 7.04 (1H, d, J = 10.0 Hz), 6.22 (s, 1H), 6.20-6.18 (m, 1H), 5.23-5.19 (m, 1H), 4.99 (t, 2H, J = 6.8 Hz), 4.57 (t, 2H, J = 6.4 Hz), 3.75 (d, 2H, J = 6.0 Hz), 2.76 (s, 3H), 2.59 (s, 3H), 1.57-1.52 (m, 12 H), 1.41 (s, 9H), 1.36-1.25 (m, 3H), 1.03-0.97 (m, 3H), 0.68-0.64 (m, 2H). MS: 522 (M+1). 1/32 ¹H-NMR (CDCl₃, 400 MHz) δ: 7.43 (d, 1H, J = 1.2 Hz), 7.29 (d, 1H, J = 8.0 Hz), 7.16 (dd, 1H, J = 7.6 Hz, 1.6 Hz), 6.21-6.19 (m, 2H), 5.82-5.79 (m, 1H), 5.20-5.19 (m, 1H), 4.99 (t, 2H, J = 6.8 Hz), 4.58 (t, 2H, J = 6.4 Hz), 3.76 (d, 2H, J = 7.2 Hz), 3.28 (d, 2H, J = 6.4 Hz), 2.60 (s, 3H), 1.59-1.56 (m, 3H), 1.44 (s, 9H), 1.42-1.33 (m, 3H), 1.02-0.93 (m, 12H), 0.68-0.64 (m, 2H). MS: 522 (M+1) 1/33 ¹H-NMR (CDCl₃, 400 MHz) δ: 7.43 (d, 1H, J = 1.6 Hz), 7.17-7.10 (m, 2H), 6.24-6.17 (m, 2H), 5.24-5.19 (m, 1H), 4.99 (t, 2H, J = 6.8 Hz), 4.57 (t, 2H, J = 6.4 Hz), 4.20 (d, 1H, J = 14.0 Hz), 3.75 (d, 2H, J = 6.0 Hz), 3.14 (s, 3H), 2.63 (d, 1H, J = 14.4 Hz), 2.60 (s, 3H), 1.57-1.52 (m, 3H), 1.43-1.31 (m, 12H), 1.08 (s, 9H), 1.03-0.97 (m, 3H), 0.68-0.64 (m, 2H). MS: 536 (M+1). 1/34 ¹H-NMR (CDCl₃, 400 MHz) δ: 7.43 (s, 1H), 7.16 (d, 1H, J = 8.0 Hz), 7.09 (1H, d, J = 7.6 Hz), 6.24 (s, 1H), 6.19 (d, 1H, J = 7.6 Hz), 5.23-5.19 (m, 1H), 4.99 (t, 2H, J = 6.8 Hz), 4.57 (t, 2H, J = 6.4 Hz), 4.12 (m, 1H), 3.75 (d, 2H, J = 6.0 Hz), 3.38-3.35 (m, 1H), 3.27-3.23 (m, 1H), 3.07-3.05 (m, 1H), 2.60 (s, 3H), 1.76-1.67 (m, 4H), 1.63-1.45 (m, 5H), 1.41 (s, 9H), 1.36-1.25 (m, 3H), 1.03-0.97 (m, 3H), 0.68-0.64 (m, 2H). MS: 520 (M+1). 1/35 ¹H-NMR (400 MHz, DMSO-d₆) δ: 7.35 (s, 1H), 7.32-7.28 (t, J = 6.2 Hz, 1H), 7.16-7.15 (d, J= 1.6 Hz, 2H), 6.53 (s, 1H), 3.77-3.74 (d, J = 7.2 Hz, 2H), 3.25-3.23 (d, J = 6.0 Hz, 2H), 3.13 (s, 3H), 2.52 (s, 3H), 1.46-1.43 (d, J = 10.4 Hz, 3H), 1.31-1.22 (m, 21H), 1.08 (s, 6H), 0.99-0.86 (m, 3H), 0.68-0.60 (m, 2H). MS: 495.2 (M+1). 1/36 ¹H-NMR (400 MHz, CDCl₃) δ: 7.36-7.34 (t, J = 1.6 Hz, 1H), 7.15-7.14 (d, J = 2.0 Hz, 2H), 7.01-6.98 (d, J = 8.8 Hz, 1H), 6.50 (s, 1H), 4.37 (s, 1H), 3.93-3.89 (m, 1H), 3.76-3.73 (d, J = 7.2 Hz, 2H), 2.51 (s, 3H), 1.46-1.44 (t, J = 4.6 Hz, 3H), 1.31-1.23 (m, 21H), 1.09-1.07 (t, J = 3.8 Hz, 3H), 0.95-0.89 (m, 3H), 0.66-0.60 (m, 2H). MS: 495.2 (M+1). 1/37 ¹H-NMR (400 MHz, DMSO-d₆) δ: 7.34-7.33 (d, J = 1.6 Hz, 1H), 7.16-7.15 (d, J = 2.0 Hz, 2H), 6.04 (s, 1H), 3.77-3.29 (m, 7H), 2.26 (d, 3H), 1.46-1.40 (m, 7H), 1.30-1.22 (m, 18H), 1.14 (s, 3H), 0.94-0.88 (m, 3H), 0.66-0.63 (m, 2H). MS: 507.2 (M+1). 1/38 ¹H-NMR (CDCl₃, 400 MHz) δ: 0.70 (2H, m), 0.86 (2H, m), 1.02 (5H, m), 1.39 (12H, s), 1.57 (3H, m), 1.91 (2H, t, J = 4.8 Hz), 2.57 (3H, s), 3.64 (2H, d, J = 7.2 Hz), 4.34 (2H, t, J = 4.8 Hz), 4.57 (2H, t, J = 6.4 Hz), 4.98 (2H, t, J = 7.2 Hz), 5.21-5.24 (1H, m), 6.11 (1H, s), 6.15 (1H, d, J = 7.2 Hz), 6.43 (1H, d, J = 2.0 Hz), 6.97 (1H, d, J = 1.6 Hz). MS: 491 (M+1). 1/39 ¹H-NMR (CDCl₃, 400 MHz) δ: 0.70 (2H, m), 0.85 (2H, m), 1.01 (5H, m), 1.23 (7H, s), 1.38 (12H, s), 1.56 (3H, m), 1.90 (2H, t, J = 5.2 Hz), 2.59 (3H, s), 3.28 (1H, s), 3.38 (2H, d, J = 6.0 Hz), 3.64 (2H, d, J = 7.2 Hz), 4.33 (2H, t, J = 5.2 Hz), 6.11-6.13 (2H, m), 6.43 (1H, d, J = 1.6 Hz), 6.97 (1H, d, J = 1.6 Hz). MS: 507 (M+1). 1/40 ¹H-NMR (CDCl₃, 400 MHz) δ: 0.64-0.72 (2H, m), 0.83-0.88 (2H, m), 0.98-1.03 (5H, m), 1.35-1.49 (12H, s), 1.57-1.65 (12H, m), 1.90 (2H, t, J = 5.2 Hz), 2.59 (3H, s), 3.39 (2H, d, J = 6.8 Hz), 3.63 (4H, d, J = 7.2 Hz), 4.33 (2H, t, J = 4.8 Hz), 5.75 (1H, t, J = 6.0 Hz), 6.06 (1H, s), 6.43 (1H, d, J = 2.0 Hz), 6.97 (1H, d, J = 2.0 Hz). MS: 521 (M+1). 1/41 ¹H-NMR (CDCl₃, 400 MHz) δ: 0.68-0.70 (2H, m), 0.84-0.87 (2H, m), 1.00-1.03 (5H, m), 1.39 (12H, s), 1.59 (9H, s), 1.90 (2H, t, J = 5.6 Hz), 2.48 (2H, d, J = 4.0 Hz), 2.55 (2H, t, J = 6.0 Hz), 2.60 (3H, s), 3.48 (2H, d, J = 5.6 Hz), 3.63 (2H, d, J = 7.6 Hz), 3.70 (4H, t, J = 4.4 Hz), 4.34 (2H, t, J = 5.2 Hz), 6.11 (1H, s), 6.30 (1H, d, J = 3.6 Hz), 6.45 (1H, d, J = 2.0 Hz), 6.99 (1H, d, J = 2.0 Hz). MS: 548 (M+1). 1/42 ¹H-NMR (CDCl₃, 400 MHz) δ: 0.64-0.74 (6H, m), 0.85-0.88 (2H, m), 1.00-1.03 (5H, m), 1.33-1.42 (6H, m), 1.56 (3H, m), 1.90-1.92 (2H, t, J = 10.0 Hz), 2.57 (3H, s), 3.64-3.66 (2H, d, J = 7.2 Hz), 4.38-4.40 (2H, t, J = 10.4 Hz), 4.55-4.58 (2H, t, J = 13.2 Hz), 4.96-5.00 (2H, t, J = 14.4 Hz), 5.20-5.22 (1H, m), 6.10 (1H, s), 6.13-6.15 (1H, m), 6.43 (1H, s), 6.97 (1H, s). MS: 489 (M+1)⁺. 1/43 ¹H-NMR (CDCl₃, 400 MHz) δ: 0.63-0.66 (m, 2H), 0.76-0.77 (m, 2H), 0.86-0.89 (m, 2H), 0.98-0.99 (m, 3H), 1.33-1.43 (m, 3H), 1.47 (s, 3H), 1.52-1.56 (m, 5H), 1.58 (s, 6H), 1.75 (s, 2H), 2.61 (s, 3H), 3.49-3.55 (t, 2H, J = 12.0 Hz), 3.72-3.74 (d, 2H, J = 8.0 Hz), 3.96-3.99 (m, 2H), 4.15-4.17 (m, 1H), 5.60-5.62 (d, 1H, J = 8.0 Hz), 6.17 (s, 1H), 7.07 (s, 1H), 7.20 (s, 1H), 7.39 (s, 1H). MS: 493 (M+1). 1/44 ¹H-NMR (CDCl₃, 400 MHz) δ: 0.61-0.64 (m, 2H), 0.75-0.77 (m, 2H), 0.86-0.89 (m, 2H), 0.98-0.99 (m, 3H), 1.32-1.37 (m, 3H), 1.43 (s, 3H), 1.47-1.53 (m, 11H), 1.96-2.00 (m, 2H), 2.61 (s, 3H), 3.08 (s, 1H), 3.49-3.55 (t, 2H, J = 12.0 Hz), 3.73-3.75 (d, 2H, J = 8.0 Hz), 3.96-3.99 (m, 2H), 4.15-4.17 (m, 1H), 5.60-5.62 (d, 1H, J = 8.0 Hz), 6.17 (s, 1H), 7.07 (s, 1H), 7.15 (s, 1H), 7.26 (s, 1H). MS: 507 (M+1). 1/45 ¹H-NMR (DMSO-d₆, 400 MHz) δ: 8.74 (s, 1H), 7.72 (d, 2H), 7.52 (d, 2H), 7.17 (m, 1H), 6.66 (m, 1H), 6.60 (s, 1H), 3.85 (m, 2H), 2.53 (s, 3H), 1.55-1.40 (m, 3H), 1.35-1.20 (m, 3H), 1.00-0.80 (m, 3H), 0.70-0.55 (m, 2H). MS: 463 (M+1). 1/46 ¹H-NMR (CDCl₃, 400 MHz) δ: 7.09 (s, 2H), 6.16 (s, 1H), 6.12 (m, 1H), 5.26 (s, 1H), 3.68-3.62 (m, 2H), 3.61-3.56 (m, 2H), 3.54-3.51 (m, 2H), 3.36 (s, 3H), 2.61 (s, 3H), 1.65-1.50 (m, 3H), 1.45 (s, 18H), 1.40-1.30 (m, 3H), 1.05-0.95 (m, 3H), 0.75-0.60 (m, 2H). MS: 483 (M+1). 1/47 ¹H-NMR (CDCl₃, 400 MHz) δ: 7.75-7.70 (m, 2H), 7.51 (m, 1H), 7.44-7.42 (m, 1H), 6.25 (s, 1H), 5.40 (br s, 2H), 3.74 (d, 2H), 2.60 (s, 3H), 1.60-1.45 (m, 3H), 1.35-1.20 (m, 3H), 1.00-0.90 (m, 3H), 0.65-0.50 (m, 2H). MS: 463 (M+1). 1/48 ¹H-NMR (400 MHz, CDCl₃) δ: 7.08 (s, 2H), 6.15 (s, 1H), 5.88-5.92 (t, 1H), 5.28 (s, 1H), 4.01-4.08 (m, 2H), 3.65-3.67 (d, 2H, J = 8.0 Hz), 2.60 (s, 3H), 1.52-1.56 (m, 4H), 1.45 (s, 18H), 1.34-1.37 (m, 2H), 0.96-1.03 (m, 3H), 0.67-0.73 (m, 2H). MS: 507 (M+1). 1/49 ¹H-NMR (400 MHz, CDCl₃) δ: 7.57-7.59 (d, 2H, J = 8.0 Hz), 7.48-7.50 (d, 1H, J = 8.0 Hz), 6.24 (s, 1H), 5.39-5.43 (m, 2H), 3.74-3.76 (d, 2H, J = 8.0 Hz), 2.56-2.63 (m, 6H), 1.54-1.57 (m, 4H), 1.25-1.39 (m, 2H), 1.28 (t, 3H), 0.83-1.05 (m, 3H), 0.58-0.64 (m, 2H). MS: 352 (M+1). 1/50 ¹H-NMR (400 MHz, CDCl₃) δ: 6.91-6.93 (d, 1H, J = 8.0 Hz), 6.87-6.89 (d, 1H, J = 8.0 Hz), 6.15 (s, 1H), 5.36-5.39 (m, 2H), 4.28 (s, 2H), 3.68-3.70 (d, 2H, J = 8.0 Hz), 2.61-2.65 (q, 2H), 2.60 (s, 3H), 1.50-1.59 (m, 4H),1.40-1.45 (m, 2H), 1.38 (s, 6H), 1.28 (m, 3H), 0.98-1.18 (m, 3H), 0.60-0.69 (m, 2H). MS: 395 (M+1). 1/51 ¹H-NMR (400 MHz, CDCl₃) δ: 7.90 (s, 1H), 7.40 (m, 1H), 7.10 (m, 1H), 6.18 (s, 1H), 3.70 (d, 1H), 3.38 (s, 3H), 2.60 (s, 3H), 1.57-1.50 (m, 3H), 1.38-1.25 (m, 21H), 1.00-0.90 (m, 3H), 0.70-0.60 (m, 2H). MS (m/z): 487 (M+1). 1/52 ¹H-NMR (400 MHz, CDCl₃) δ: 7.30 (s, 1H), 7.08 (m, 2H), 6.04 (s, 1H), 3.63 (m, 10H), 2.32 (s, 3H), 1.75 (m, 1H), 1.45 (m, 3H), 1.26 (s, 21H), 0.93 (m, 3H), 0.57 (m, 2H). MS (m/z): 479.2 (M+1). 1/53 ¹H-NMH (500 MHz, CDCl₃) δ: 7.33 (s, 1H), 7.07 (m, 2H), 6.16 (s, 1H), 6.13 (m, 1H), 5.15 (m, 1H), 4.91 (t, J = 7.0 Hz, 2H), 4.51 (t, J = 6.5 Hz, 2H), 3.64 (d, J = 7.0 Hz, 2H), 2.53 (s, 3H), 1.45 (m, 3H), 1.28 (s, 21H), 0.92 (m, 3H), 0.57 (m, 2H). MS (m/z): 465.2 (M+1). 1/54 ¹H-NMR (500 MHz, CDCl₃) δ: 7.31 (s, 1H), 7.07 (m, 2H), 6.18 (m, 1H), 6.15 (s, 1H), 3.71 (m, 2H), 3.64 (d, J = 7.0 Hz, 2H), 3.48 (m, 2H), 2.54 (s, 3H), 1.45 (m, 3H), 1.27 (s, 21H), 0.92 (m, 3H), 0.57 (m, 2H). MS (m/z): 453.2 (M+1). 1/55 ¹H-NMR (400 MHz, CDCl₃) δ: 7.31 (s, 1H), 7.07 (m, 2H), 6.16 (m, 2H), 3.64 (d, J = 7.2 Hz, 2H), 3.32 (d, J = 6.0 Hz, 2H), 2.54 (s, 3H), 1.45 (m, 3H), 1.27 (s, 21H), 1.18 (s, 6H), 0.92 (m, 3H), 0.57 (m, 2H). MS (m/z): 481.2 (M+1). 1/56 ¹H-NMR (500 MHz, CDCl₃) δ: 7.38 (m, 1H), 7.14 (m, 2H), 6.87 (br s, 1H), 6.35 (s, 1H), 3.70 (d, J = 7.5 Hz, 2H), 3.60 (m, 2H), 3.01 (m, 2H), 2.67 (s, 6H), 2.57 (s, 3H), 1.52 (m, 3H), 1.33 (s, 21H), 0.98 (m, 3H), 0.64 (m, 2H). MS (m/z): 480.2 (M+1). 1/57 ¹H-NMR (500 MHz, CDCl₃) δ: 7.26 (s, 1H), 7.01 (m, 2H), 6.26 (br s, 1H), 6.14 (s, 1H), 4.05 (m, 2H), 3.58 (d, J = 7.5 Hz, 2H), 2.47 (s, 3H), 1.40 (m, 3H), 1.20 (s, 21H), 0.87 (m, 3H), 0.52 (m, 2H). MS (m/z): 467.2 (M+1). 1/58 ¹H-NMR (400 MHz, CDCl₃) δ: 7.32 (s, 1H), 7.05 (m, 2H), 6.25 (br s, 1H), 6.05 (s, 1H), 5.18 (br s, 1H), 3.64 (d, J = 6.8 Hz, 4H), 2.54 (s, 3H), 1.45 (m, 3H), 1.24 (s, 21H), 0.92 (m, 7H), 0.57 (m, 2H). MS (m/z): 479.2 (M+1). 1/59 ¹H-NMR (400 MHz, CDCl₃) δ: 7.32 (s, 1H), 7.07 (m, 2H), 6.15 (m, 2H), 3.64 (d, J = 6.8 Hz, 2H), 3.28-3.48 (m, 4H), 2.54 (s, 3H), 1.45 (m, 3H), 1.24 (m, 24H), 0.92 (m, 3H), 0.57 (m, 2H). MS (m/z): 467.2 (M+1). 1/60 ¹H-NMR (400 MHz, CDCl₃) δ: 7.31 (s, 1H), 7.07 (m, 2H), 6.20 (br s, 1H), 6.15 (s, 1H), 3.93 (m, 1H), 3.64 (d, J = 7.2 Hz, 2H), 3.45 (m, 2H), 3.22 (m, 1H), 2.53 (s, 3H), 1.45 (m, 3H), 1.27 (s, 21H), 1.14 (m, 3H), 0.91 (m, 3H), 0.55 (m, 2H). MS (m/z): 467.2 (M+1). 1/61 ¹H-NMR (400 MHz, CDCl₃) δ: 7.40 (m, 1H), 7.12 (m, 2H), 6.18 (s, 1H), 6.10 (br s, 1H), 3.71 (d, J = 7.2 Hz, 2H), 3.47 (m, 1H), 2.59 (s, 3H), 1.86 (m, 1H), 1.52 (m, 3H), 1.30 (s, 22H), 0.98 (m, 3H), 0.64 (m, 2H). MS (m/z): 585.2 (M+1). 1/62 ¹H-NMR (400 MHz, DMSO-d₆) δ: 7.72-7.69 (t, J = 5.4 Hz, 1H), 7.47 (s, 1H), 7.23 (s, 2H), 6.57 (s, 1H), 3.85-3.83 (d, J = 6.8 Hz, 2H), 3.65-3.62 (t, J = 6.0 Hz, 1H), 3.51-3.48 (t, J = 6.0 Hz, 2H), 3.39-3.36 (t, J = 6.0 Hz, 2H), 2.60 (s, 3H), 1.54-1.51 (d, J = 8.8 Hz, 3H), 1.39-1.29 (m, 21H), 1.17-1,16 (d, J = 6.0 Hz, 6H), 0.99-0.96 (d, J = 12.4 Hz, 3H), 0.76-0.70 (t, J = 10.6 Hz, 2H). MS (m/z): 495 (M+1). 1/63 ¹H-NMR (400 MHz, DMSO-d₆) δ: 7.65-7.62 (t, J = 4.8 Hz, 1H), 7.34 (s, 1H), 7.15 (s, 2H), 6.49 (s, 1H), 4.61-4.59 (t, J = 5.0 Hz, 1H), 3.76-3.74 (d, J = 6.4 Hz, 2H), 3.51-3.43 (m, 6H), 3.34 (s, 2H), 2.52 (s, 3H), 1.44-1.42 (d, J = 4.4 Hz, 3H), 1.30 (s, 18H), 1.24-1.21 (d, J = 13.2 Hz, 3H), 0.93-0.87 (t, J = 10.4 Hz, 3H), 0.64-0.61 (d, J = 10.8 Hz, 2H). MS (m/z): 497 (M+1). 1/64 ¹H-NMR (400 MHz, DMSO-d₆) δ: 7.67-7.64 (t, J = 5.2 Hz, 1H), 7.35 (s, 1H), 7.16 (s, 2H), 6.51 (s, 1H), 3.77-3.76 (d, J = 6.8 Hz, 2H), 3.42-3.39 (t, J = 5.6 Hz, 2H), 3.35 (s, 2H), 3.26 (s, 3H), 2.53 (s, 3H), 1.45-1.43 (d, J = 8.8 Hz, 3H), 1.31 (s, 18H), 1.25-1.22 (d, J = 13.2 Hz, 3H), 0.94-0.89 (t, J = 10.6 Hz, 3H), 0.68-0.60 (m, 2H). MS (m/z): 467 (M+1). 1/65 ¹H-NMR (400 MHz, DMSO-d₆) δ: 7.70-7.68 (d, J = 4.8 Hz, 1H), 7.42 (s, 1H), 7.23 (s, 2H), 6.60 (s, 1H), 4.57-4.54 (t, J = 5.0 Hz, 1H), 3.84-3.82 (d, J = 7.2 Hz, 2H), 3.54-3.49 (m, 2H), 3.32-3.28 (m, 2H), 2.58 (s, 3H), 1.71-1.68 (t, J = 6.4 Hz, 2H), 1.53-1.51 (d, J = 9.6 Hz, 3H), 1.38-1.29 (m, 21H), 1.01-0.96 (t, J = 10.0 Hz, 3H), 0.75-0.70 (t, J = 10.4 Hz, 2H). MS (m/z): 467 (M+1). 1/66 ¹H-NMR (400 MHz, DMSO-d₆) δ: 7.60-7.58 (d, J = 5.2 Hz, 1H), 7.35 (s, 1H), 7.15 (s, 2H), 6.48 (s, 1H), 4.39-4.37 (t, J = 5.2 Hz, 1H), 3.77-3.75 (d, J = 7.2 Hz, 2H), 3.43-3.38 (m, 2H), 3.18-3.14 (m, 2H), 2.52 (s, 3H), 1.48-1.43 (t, J = 10.0 Hz, 7H), 1.31-1.21 (m, 21H), 0.94-0.89 (t, J = 10.4 Hz, 3H), 0.65-0.62 (d, J = 11.2 Hz, 2H). MS (m/z): 481 (M+1). 1/67 ¹H-NMR (400 MHz, DMSO-d₆) δ: 7.58 (s, 1H), 7.33 (s, 1H), 7.14 (s, 2H), 6.48 (s, 1H), 4.34 (s, 1H), 3.75-3.74 (d, J = 6.0 Hz, 2H), 3.39-3.38 (d, J = 5.2 Hz, 2H), 3.12-3.14 (d, J = 6.0 Hz, 2H), 2.51 (s, 3H), 1.45-1.43 (d, J = 5.6 Hz, 7H), 1.30 (s, 20H), 1.24-1.21 (d, J = 12.4 Hz, 3H), 0.91-0.88 (d, J = 11.2 Hz, 3H), 0.64-0.61 (d, J = 10.4 Hz, 2H). MS (m/z): 495 (M+1). 1/68 ¹H-NMR (400 MHz, DMSO-d₆) δ: 12.13 (s, 1H), 7.70-7.67 (t, J = 5.2 Hz, 1H), 7.35 (s, 1H), 7.15 (s, 2H), 6.47 (s, 1H), 3.77-3.75 (d, J = 6.8 Hz, 2H), 3.38-3.35 (t, J = 6.0 Hz, 2H), 2.52-2.45 (m, 5H), 1.46-1.43 (d, J = 4.6 Hz, 3H), 1.31-1.21 (t, J = 9.8 Hz, 21H), 0.94-0.89 (t, J = 5.0 Hz, 3H), 0.65-0.62 (d, J = 10.8 Hz, 2H). MS (m/z): 481 (M+1). 1/69 ¹H-NMR (400 MHz, DMSO-d₆) δ: 12.03 (s, 1H), 7.66-7.63 (t, J = 5.2 Hz, 1H), 7.35 (s, 1H), 7.15 (s, 2H), 6.49 (s, 1H), 3.77-3.75 (d, J = 6.8 Hz, 2H), 3.20-3.15 (m, 2H), 2.52-2.50 (d, J = 6.8 Hz, 3H), 2.26-2.23 (t, J = 7.2 Hz, 2H), 1.73-1.66 (m, 2H), 1.46-1.44 (d, J = 4.4 Hz, 3H), 1.31-1.15 (m, 21H), 0.98-0.89 (m, 3H), 0.65-0.62 (m, 2H). MS (m/z): 495 (M+1). 1/70 ¹H-NMR (400 MHz, DMSO-d₆) δ: 7.60 (s, 1H), 7.35 (s, 1H), 7.15 (s, 2H), 6.46 (s, 1H), 3.77-3.75 (d, J = 7.2 Hz, 2H), 3.60 (s, 4H), 3.32 (s, 4H), 2.52-2.40 (t, 7H), 1.46-1.44 (d, J = 9.2 Hz, 3H), 1.31 (s, 18H), 1.24-1.21 (d, J = 13.6 Hz, 3H), 0.91-0.88 (m, 3H), 0.68-0.60 (m,2H). MS (m/z): 522 (M+1). 1/71 ¹H-NMR (400 MHz, DMSO-d₆) δ: 7.68-7.66 (t, J = 5.4 Hz, 1H), 7.35 (s, 1H), 7.15 (s, 2H), 6.46 (s, 1H), 3.77-3.75 (d, J = 6.8 Hz, 2H), 3.58-3.57 (d, J = 4.0 Hz, 4H), 3.22-3.18 (m, 2H), 2.52-2.50 (d, J = 6.0 Hz, 3H), 2.39-2.34 (t, J = 10.6 Hz, 6H), 1.66-1.62 (t, J = 6.6 Hz, 2H), 1.46-1.43 (d, J = 9.2 Hz, 3H), 1.31-1.21 (m, 21H), 0.91-0.88 (d, J = 12.0 Hz, 3H), 0.67-0.62 (t, J = 10.8 Hz, 2H). MS (m/z): 536 (M+1). 1/72 ¹H-NMR (400 MHz, DMSO-d₆) δ: 11.97 (s, 1H), 7.63-7.60 (t, J = 5.6 Hz, 1H), 7.37 (s,1H), 7.18-7.17 (d, J = 1.2 Hz, 2H), 6.50 (s, 1H), 3.79-3.77 (d, J = 7.2 Hz, 2H), 3.19-3.15 (m, 2H), 2.54-2.52 (m, 3H), 2.25-2.21 (t, J = 7.4 Hz, 2H), 1.56-1.46 (m, 7H), 1.33-1.24 (m, 23H), 0.96-0.88 (m, 3H), 0.69-0.67 (m, 2H). MS (m/z): 523 (M+1). 1/73 ¹H-NMR (400 MHz, DMSO-d₆) δ: 12.01 (s, 1H), 7.63-7.60 (t, J = 5.6 Hz, 1H), 7.35 (s, 1H), 7.16-7.15 (d, J = 1.2 Hz, 2H), 6.48 (s, 1H), 3.77-3.75 (d, J = 6.8 Hz, 2H), 3.18-3.15 (t, J = 6.2 Hz, 2H), 2.52-2.51 (d, J = 4.8 Hz, 3H), 2.25-2.21 (t, J = 6.8 Hz, 2H), 1.50-1.43 (m, 7H), 1.31-1.25 (m, 21H), 0.94-0.85 (m, 3H), 0.63-0.60 (m, 2H). MS (m/z): 509 (M+1). 1/74 ¹H-NMR (400 MHz, DMSO-d₆) δ: 7.67 (s, 1H), 7.39 (s, 1H), 7.20 (s, 2H), 6.54 (s, 1H), 3.81-3.80 (d, J = 6.0 Hz, 2H), 3.62 (s, 4H), 3.23 (s, 2H), 2.57 (s, 3H), 2.45 (s, 4H), 2.39 (s, 2H), 1.52 (s, 7H), 1.35-1.26 (m, 21H), 0.96 (s, 3H), 0.69-0.67 (d, J = 10.4 Hz, 2H). MS (m/z): 550 (M+1). 1/75 ¹H-NMR (400 MHz, DMSO-d₆) δ: 7.61-7.58 (t, J = 5.8 Hz, 1H), 7.35 (s, 1H), 7.15-7.15 (d, J = 1.6 Hz, 2H), 6.48 (s, 1H), 3.77-3.75 (d, J = 6.8 Hz, 2H), 3.55-3.54 (d, J = 4.4 Hz, 4H), 3.18-3.13 (m, 2H), 2.51-2.51 (d, J = 3.2 Hz, 3H), 2.33 (s, 4H), 2.28-2.24 (t, J = 7.2 Hz, 2H), 1.49-1.40 (m, 7H), 1.31-1.21 (m, 23H), 0.92-0.88 (d, J = 12.8 Hz, 3H), 0.67-0.62 (t, J = 10.4 Hz, 2H). MS (m/z): 564 (M+1). 1/76 ¹H-NMR (500 MHz, CDCl₃) δ: 0.59 (m, 2H), 0.80 (m, 3H), 1.11 (m, 14H), 1.47 (m, 3H), 1.80-2.54 (m, 8H), 3.67 (d, 2H), 5.40 (br s, 2H), 6.14 (s, 1H), 6.94 (s, 1H), 7.08 (m, 2H). MS (m/z): 407 (M+1). 1/77 ¹H-NMR (300 MHz, DMSO-d₆) δ: 8.22 (d, J = 6.6 Hz, 1H), 7.14 (d, J = 7.5 Hz, 2H), 6.59 (s, 1H), 4.96 (m, 1H), 4.74 (m, 2H), 4.56 (m, 2H), 3.74 (d, J = 6.6 Hz, 2H), 2.50 (s, 3H), 1.49 (m, 24H), 0.98 (m, 3H), 0.71 (m, 2H). MS (m/z): 483 (M+1). 1/78 ¹H-NMR (400 MHz, CDCl₃) δ: 7.60 (s, 1H), 7.53 (s, 1H), 7.41 (s, 1H), 6.28 (s, 1H), 6.17 (d, 1H), 5.23 (m, 1H), 4.99 (m, 2H), 4.58 (t, 2H), 3.73 (d, 2H), 2.61 (s, 3H), 1.56 (s, 6H), 1.32 (m, 9H), 1.00 (m, 3H), 0.63 (m, 2H). MS (m/z): 477 (M+1). 1/79 ¹H-NMR (400 MHz, CDCl₃) δ: 7.47 (s, 1H), 7.37 (s, 2H), 6.27 (s, 1H), 6.16 (d, 1H), 5.21 (m, 1H), 4.99 (m, 2H), 4.58 (m, 2H), 3.73 (d, 2H), 2.60 (s, 3H), 1.54 (m, 4H), 1.46 (s, 3H), 1.33 (m, 3H), 1.01 (m, 2H), 1.00 (m, 2H), 0.84 (m, 2H), 0.66 (m, 2H). MS (m/z): 475 (M+1). 1/80 ¹H-NMR (CDCl₃, 300 MHz) δ: 7.07 (s, 1H), 6.92 (d, J = 1.5 Hz, 2H), 6.10 (m, 2H), 5.15 (m, 1H), 4.91 (t, 2H), 4.50 (t, 2H), 3.64 (d, J = 6.9 Hz, 2H), 2.52 (s, 3H), 1.47 (m, 3H), 1.18-1.46 (m, 9H), 0.94 (m, 3H), 0.76-0.81 (m, 10H). MS (m/z): 461 (M+1). 1/81 ¹H-NMR (DMSO-d₆, 400 MHz) δ: 8.22 (d, 1H), 7.20 (s, 1H), 7.16 (s, 1H), 6.99 (s, 1H), 6.59 (s, 1H), 4.93 (m, 1H), 4.72 (t, 2H), 4.55 (t, 2H), 3.76 (t, 2H), 2.50 (s, 3H), 1.45 (m, 3H), 1.40 (s, 3H), 1.31 (s, 9H), 1.23 (m, 3H), 0.95 (m, 3H), 0.84 (m, 2H), 0.76 (m, 2H), 0.65 (m, 2H). MS (m/z): 463 (M+1). 1/82 ¹H-NMR (400 MHz, DMSO-d₆) δ: 7.58 (t, 1H), 7.19 (s, 1H), 7.14 (s, 1H), 6.97 (s, 1H), 6.48 (s, 1H), 4.34 (t, 1H), 3.75 (d, 2H), 3.69 (m, 2H), 3.15 (m, 2H), 2.50 (m, 3H), 1.40-1.48 (m, 10H), 1.27 (m, 14H), 0.77-0.96 (m, 9H). MS (m/z): 493 (M+1). 1/83 ¹H-NMR (400 MHz, DMSO-d₆) δ: 7.57 (t, 1H), 7.19 (s, 1H), 7.13 (s, 1H), 6.96 (s, 1H), 6.46 (s, 1H), 3.75 (d, 2H), 2.73 (m, 1H), 2.50 (m, 3H), 1.21-1.47 (m, 18H), 0.74-0.95 (m, 13H). MS (m/z): 447 (M+1). 1/84 ¹H-NMR (400 MHz, DMSO-d₆) δ: 7.41 (d, 1H), 7.20 (s, 1H), 7.14 (s, 1H), 6.97 (s, 1H), 6.53 (s, 1H), 3.95 (m, 1H), 3.87 (d, 2H), 3.85 (d, 2H), 3.35 (d, 2H), 2.56 (m, 3H), 1.71 (d, 2H), 1.45-1.68 (m, 8H), 1.22-1.30 (m, 12H), 0.59-0.96 (m, 9H). MS (m/z): 491 (M+1). 1/85 ¹H-NMR (400 MHz, DMSO-d₆) δ: 7.33 (t, 1H), 7.19 (d, 2H), 7.13 (s, 1H), 6.96 (s, 1H), 6.85 (s, 1H), 6.41 (s, 1H), 3.74 (d, 2H), 3.28 (d, 2H), 2.50 (m, 3H), 1.22-1.46 (m, 18H), 0.75-0.95 (m, 15H). MS (m/z): 506 (M+1). 1/86 ¹H-NMR (400 MHz, DMSO-d₆) δ: 7.80 (t, 1H), 7.20 (d, 2H), 6.98 (s, 1H), 6.53 (s, 1H), 4.47 (d, 2H), 4.15 (d, 2H), 3.75 (d, 2H), 3.33 (s, 2H), 2.50 (m, 3H), 1.23-1.47 (m, 21H), 0.63-0.96 (m, 9H). MS (m/z): 491 (M+1). 1/87 ¹H-NMR (400 MHz, DMSO-d₆) δ: 7.46 (t, 1H), 7.19 (d, 2H), 6.98 (s, 1H), 6.53 (s, 1H), 4.66 (s, 1H), 3.76 (d, 2H), 3.16 (d, 2H), 2.51 (m, 3H), 1.24-1.47 (m, 18H), 0.63-1.08 (m, 15H). MS (m/z): 479 (M+1). 1/88 ¹H-NMR (400 MHz, DMSO-d₆) δ: 7.56 (t, 1H), 7.19 (d, 2H), 6.97 (s, 1H), 6.45 (s, 1H), 3.75 (d, 2H), 3.57 (m, 4H), 3.28 (m, 2H), 2.50 (m, 3H), 2.40 (m, 6H), 1.22-1.47 (m, 18H), 0.75-0.96 (m, 9H). MS (m/z): 520 (M+1). 1/89 ¹H-NMR (400 MHz, DMSO-d₆) δ: 7.14 (m, 3H), 6.97 (s, 1H), 6.49 (d, 2H), 3.77 (d, 2H), 2.50 (m, 3H), 1.23-1.48 (m, 18H), 0.66-0.96 (m, 9H). MS (m/z): 407 (M+1). 1/90 ¹H-NMR (400 MHz, CDCl₃) δ: 6.96 (s, 1H), 6.42 (s, 1H), 6.32 (m, 1H), 6.07 (s, 1H), 4.34 (t, 2H), 3.67 (m, 4H), 2.72 (t, 2H), 2.58 (s, 3H), 1.91 (t, 2H), 1.53 (m, 3H), 1.44 (m, 12H), 1.02 (m, 5H), 0.84 (m, 2H), 0.67 (m, 2H). MS (m/z): 507 (M+1). 1/91 ¹H-NMR (400 MHz, CDCl₃) δ: 6.97 (s, 1H), 6.43 (s, 1H), 6.29 (m, 1H), 6.09 (s, 1H), 4.34 (t, 2H), 3.63 (d, 2H), 3.52 (d, 2H), 2.59 (s, 3H), 1.90 (t, 2H), 1.57 (m, 3H), 1.38 (m, 12H), 1.25 (m, 6H), 1.01 (m, 5H), 0.83 (m, 2H), 0.67 (m, 2H). MS (m/z): 534 (M+1). 1/92 ¹H-NMR (400 MHz, CDCl₃) δ: 6.96 (s, 1H), 6.42 (s, 1H), 6.00 (s, 1H), 5.83 (br s, 1H), 4.33 (t, 2H), 3.64 (d, 2H), 2.81 (s, 1H), 2.60 (s, 3H), 1.91 (t, 2H), 1.57 (m, 3H), 1.39 (m, 12H), 1.02 (m, 5H), 0.85 (m, 4H), 0.77 (m, 2H), 0.57 (m, 2H). MS (m/z): 475 (M+1). 1/93 ¹H-NMR (400 MHz, CDCl₃) δ: 6.97 (s, 1H), 6.43 (s, 1H), 6.06 (s, 1H), 5.57 (d, 1H), 4.34 (t, 2H), 4.17 (s, 1H), 3.96 (m, 2H), 3.63 (d, 2H), 3.49 (t, 2H), 2.59 (s, 3H), 1.99 (d, 2H), 1.95 (t, 2H), 1.52 (m, 5H), 1.38 (m, 12H), 1.02 (m, 5H), 0.86 (m, 2H), 0.64 (m, 2H). MS (m/z): 519 (M+1). 1/94 ¹H-NMR (400 MHz, CDCl₃) δ: 6.97 (s, 1H), 6.43 (s, 1H), 6.05 (s, 1H), 5.83 (s, 1H), 4.34 (t, 2H), 3.99 (d, 2H), 3.64 (d, 2H), 3.37 (t, 2H), 3.26 (t, 2H), 2.59 (s, 3H), 1.91 (t, 3H), 1.84 (m, 2H), 1.57 (m, 3H), 1.34 (m, 12H), 1.02 (m, 5H), 0.86 (m, 2H), 0.69 (m, 2H). MS (m/z): 533 (M+1). 1/95 ¹H-NMR (400 MHz, CDCl₃) δ: 6.96 (s, 1H), 6.42 (s, 1H), 6.06 (s, 1H), 5.85 (d, 1H), 4.69 (s, 1H), 4.34 (t, 2H), 3.94 (m, 2H), 3.84 (m, 2H), 3.71 (d, 2H), 2.58 (s, 3H), 2.31 (m, 1H), 1.90 (m, 3H), 1.56 (m, 3H), 1.38 (m, 12H), 1.02 (m, 5H), 0.84 (m, 2H), 0.65 (m, 2H). MS (m/z): 505 (M+1). 1/96 ¹H-NMR (400 MHz, CDCl₃) δ: 6.96 (s, 1H), 6.43 (s, 1H), 6.06 (s, 1H), 5.85 (d, 1H), 4.69 (s, 1H), 4.34 (t, 2H), 3.94 (m, 2H), 3.84 (m, 2H), 3.71 (d, 2H), 2.58 (s, 3H), 2.31 (m, 1H), 1.90 (m, 3H), 1.56 (m, 3H), 1.38 (m, 12H), 1.02 (m, 5H), 0.84 (m, 2H), 0.64 (m, 2H). MS (m/z): 505 (M+1). 1/97 ¹H-NMR (400 MHz, CDCl₃) δ: 6.91 (s, 1H), 6.38 (s, 1H), 6.06 (s, 1H), 5.97 (d, 1H), 4.27 (t, 2H), 3.57 (d, 2H), 3.35 (d, 2H), 3.71 (d, 2H), 3.13 (s, 3H), 2.52 (s, 3H), 1.84 (m, 2H), 1.50 (m, 3H), 1.36 (m, 12H), 1.19 (s, 6H), 0.95 (m, 5H), 0.78 (m, 2H), 0.63 (m, 2H). MS (m/z): 521 (M+1). 1/98 ¹H-NMR (400 MHz, CDCl₃) δ: 6.89 (s, 1H), 6.31 (m, 3H), 6.03 (s, 1 H), 5.19 (s, 1H), 4.26 (t, 2H), 3.55 (d, 2H), 3.45 (d, 2H), 2.51 (s, 3H), 1.84 (t, 2H), 1.50 (m, 3H), 1.37 (m, 12H), 1.25 (s, 6H), 0.96 (m, 5H), 0.79 (m, 2H), 0.60 (m, 2H). MS (m/z): 534 (M+1). 1/99 ¹H-NMR (400 MHz, CDCl₃) δ: 6.97 (s, 1H), 6.43 (s, 1H), 6.08 (d, 2H), 4.35 (t, 2H), 3.85 (m, 4H), 3.77 (d, 2H), 3.44 (s, 2H), 2.59 (s, 3H), 1.90 (t, 2H), 1.63 (m, 7H), 1.44 (m, 12H), 1.02 (m, 5H), 1.00 (m, 2H), 0.72 (m, 2H). MS (m/z): 549 (M+1). 1/100 ¹H-NMR (400 MHz, CDCl₃) δ: 6.89 (s, 1H), 6.36 (s, 1H), 5.99 (s, 1H), 5.84 (t, 1H), 4.73 (t, 2H), 4.40 (t, 2H), 4.25 (t, 2H), 3.58 (m, 4H), 3.20 (m, 1H), 2.51 (s, 3H), 1.83 (m, 2H), 1.51 (m, 3H), 1.33 (m, 12H), 0.95 (m, 5H), 0.79 (m, 2H), 0.60 (m, 2H). MS (m/z): (M+1). 1/101 ¹H-NMR (400 MHz, CDCl₃) δ: 6.97 (s, 1H), 6.43 (s, 1H), 6.10 (s, 1H), 6.00 (t, 1H), 4.54 (d, 2H), 4.38 (d, 2H), 4.32 (t, 2H), 3.63 (d, 2H), 3.55 (d, 2H), 2.59 (s, 3H), 1.90 (m, 2H), 1.56 (m, 3H), 1.26 (m, 15H), 1.01 (m, 5H), 0.85 (m, 2H), 0.68 (m, 2H). MS (m/z): 519 (M+1). 1/102 ¹H-NMR (400 MHz, CDCl₃) δ: 6.98 (s, 1H), 6.44 (s, 1H), 6.10 (s, 1H), 5.81 (s, 1H), 4.33 (t, 2H), 3.63 (d, 2H), 3.24 (d, 2H), 2.59 (s, 3H), 1.91 (m, 2H), 1.58 (m, 3H), 1.37 (m, 12H), 1.01 (m, 6H), 0.85 (m, 2H), 0.67 (m, 2H), 0.25 (m, 2H), 0.21 (m, 2H). MS (m/z): 489 (M+1). 1/103 ¹H-NMR (400 MHz, CDCl₃) δ: 6.90 (s, 1H), 6.37 (s, 1H), 6.21 (t, 1H), 6.06 (s, 1H), 5.56 (s, 1H), 4.25 (t, 2H), 3.56 (d, 2H), 3.38 (d, 2H), 2.94 (s, 3H), 2.51 (s, 3H), 1.83 (m, 2H), 1.50 (m, 3H), 1.33 (m, 18H), 0.96 (m, 5H), 0.78 (m, 2H), 0.61 (m, 2H). MS (m/z): 584 (M+1). 1/104 ¹H-NMR (400 MHz, CDCl₃) δ: 6.89 (s, 1H), 6.35 (m, 2H), 6.03 (s, 1H), 4.27 (t, 2H), 3.84 (m, 2H), 3.57 (d, 2H), 3.27 (t, 2H), 2.90 (s, 3H), 2.51 (s, 3H), 1.84 (m, 2H), 1.58 (m, 3H), 1.30 (m, 12H), 0.97 (m, 5H), 0.78 (m, 2H), 0.61 (m, 2H). MS (m/z): 541 (M+1). 1/105 ¹H-NMR (400 MHz, CDCl₃) δ: 6.91 (s, 1H), 6.37 (s, 1H), 6.04 (t, 1H), 5.45 (s, 2H), 4.27 (t, 2H), 3.37 (d, 2H), 2.52 (s, 3H), 1.84 (m, 2H), 1.51 (m, 3H), 1.29 (m, 12H), 0.94 (m, 5H), 0.79 (m, 2H), 0.61 (m, 2H). MS (m/z): 435 (M+1). 1/106 ¹H-NMR (400 MHz, DMSO-d₆) δ: 8.22 (d, 1H), 7.49 (s, 1H), 7.18 (d, 2H), 6.59 (s, 1H), 5.05 (s, 1H), 4.94 (m, 1H), 4.71 (t, 2H), 4.55 (t, 2H), 3.77 (d, 2H), 2.50 (s, 3H), 1.44 (s, 9H), 1.31 (s, 9H), 1.21 (m, 3H), 0.92 (m, 3H), 0.59 (m, 2H). MS (m/z): 467 (M+1). 1/107 ¹H-NMR (400 MHz, CDCl₃) δ: 7.42 (s, 1H), 7.23 (s, 1H), 7.10 (s, 1H), 6.25 (s, 1H), 6.18 (d, 1H), 5.24 (m, 1H), 4.97 (t, 2H), 4.56 (t, 2H), 3.73 (d, 2H), 3.09 (s, 3H), 2.60 (s, 3H), 1.53 (m, 9H), 1.37 (m, 12H), 0.97 (m, 3H), 0.61 (m, 2H). MS (m/z): 481 (M+1). 1/108 ¹H-NMR (400 MHz, DMSO-d₆) δ: 8.22 (d, 1H), 7.26 (s, 2H), 7.13 (s, 1H), 6.61 (s, 1H), 4.98 (m, 1H), 4.73 (t, 2H), 4.53 (t, 2H), 3.78 (d, 2H), 3.57 (t, 3H), 3.51 (s, 2H), 2.36 (s, 4H), 1.45 (d, 3H), 1.24 (m, 12H), 0.86 (m, 3H), 0.56 (m, 2H). MS (m/z): 508 (M+1). 1/109 ¹H-NMR (400 MHz, DMSO-d₆) δ: 7.48 (t, 1H), 7.24 (s, 2H), 7.10 (s, 1H), 6.54 (s, 1H), 4.64 (m, 1H), 3.78 (t, 2H), 3.55 (m, 4H), 3.40 (m, 1H), 3.16 (d, 2H), 2.52 (s, 3H), 2.29 (m, 2H), 2.26 (m, 2H), 1.45 (m, 3H), 1.31 (m, 12H), 1.23 (m, 3H), 1.08 (s, 6H), 0.92 (m, 3H), 0.59 (m, 2H). MS (m/z): 538 (M+1). 1/110 ¹H-NMR (400 MHz, DMSO-d₆) δ: 7.47 (t, 1H), 7.23 (s, 1H), 7.16 (s, 1H), 7.11 (s, 1H), 6.61 (s, 1H), 3.81 (d, 2H), 3.17 (d, 2H), 2.81 (s, 3H), 2.50 (s, 3H), 1.41 (m, 15H), 1.24 (m, 3H), 1.07 (s, 6H), 0.63-0.89 (m, 8H). MS (m/z): 536 (M+1). 1/111 ¹H-NMR (400 MHz, DMSO-d₆) δ: 7.82 (s, 1H), 7.64 (s, 1H), 7.59 (s, 1H), 7.47 (m, 1H), 7.32 (s, 1H), 6.62 (s, 1H), 4.64 (s, 1H), 3.82 (d, 2H), 3.16 (d, 2H), 2.54 (s, 3H), 1.46 (m, 15H), 1.30 (m, 3H), 1.11 (s, 6H), 0.63-0.97 (m, 8H). MS (m/z): 522 (M +1). 1/112 ¹H-NMR (400 MHz, DMSO-d₆) δ: 8.28 (d, 1H), 7.68 (d, 2H), 7.48 (t, 1H), 7.34 (s, 2H), 6.63 (s, 1H), 4.64 (s, 1H), 4.13 (m, 1H), 3.83 (d, 2H), 3.16 (d, 2H), 2.49 (s, 3H), 1.17-1.48 (m, 15H), 1.08 (s, 6H), 0.63-0.90 (m, 9H). MS (m/z): 508 (M +1). 1/113 ¹H-NMR (400 MHz, CDCl₃) δ: 8.05 (s, 1H), 7.43 (s, 1H), 7.16 (s, 2H), 6.25 (t, J = 5.6 Hz, 1H), 6.23 (s, 1H), 3.93 (d, J = 6.0 Hz, 2H), 3.74 (d, J = 7.2 Hz, 2H), 2.61 (s, 3H), 1.56-1.51 (m, 4H), 1.36 (s, 18H), 1.40-1.25 (m, 4H), 1.02-0.87 (m, 3H), 0.67-0.64 (m, 2H). MS: 589 (M+1). 1/114 ¹H-NMR (400 MHz, CD₃OD) δ: 7.34 (s, 1H), 7.10 (m, 2H), 6.41 (s, 1H), 4.96 (m, 1H), 4.62 (m, 2H), 4.58 (t, J = 6.8 Hz, 2H), 3.93-3.70 (m, 2H), 2.44 (m, 3H), 1.47-1.26 (m, 1H), 1.26-1.02 (m, 24H), 0.70-0.42 (m, 6H). MS: 479.4 (M+1)⁺. 1/115 ¹H-NMR (400 MHz, CDCl₃) δ: 7.42 (s, 1H), 7.18 (s, 2H), 6.29-6.26 (m, 2H), 5.26 (m, 1H), 5.01 (t, J = 6.8 Hz, 2H), 4.61 (t, J = 6.4 Hz, 2H), 3.73 (d, J = 7.6 Hz, 2H), 2.62 (s, 3H), 1.27-1.55 (m, 27H), 0.89-1.21 (m, 4H). MS: 479.4 (M+1)⁺. 1/116 ¹H-NMR (400 MHz, DMSO-d₆) δ: 8.23 (d, J = 5.2 Hz, 1H), 7.40 (s, 1H), 7.17 (s, 2H), 6.58 (s, 1H), 4.97 (m, 1H), 4.72 (t, J = 6.8 Hz, 2H), 4.55 (t, J = 6.4 Hz, 2H), 3.84 (m, 2H), 2.53 (m, 3H), 1.35-1.56 (m, 27H), 0.84 (m, 2H). MS: 465.4 (M+1)⁺. 1/117 ¹H-NMR (400 MHz, CDCl₃) δ: 7.29 (s, 1H), 7.05 (s, 2H), 6.26 (m, 1H), 6.16 (m, 1H), 5.10 (m, 1H), 4.85 (t, J = 6.8 Hz, 2H), 4.47 (m, 2H), 3.53-3.84 (m, 2H), 2.50 (m, 3H), 1.12-1.89 (m, 23H), 0.27-0.85 (m, 6H). MS: 477.1 (M+1)⁺. 1/118 ¹H-NMR (400 MHz, CDCl₃) δ: 7.28 (m, 1H), 7.09 (m, 2H), 6.95 (m, 4H), 6.22-6.18 (m, 2H), 5.18 (m, 1H), 4.93 (t, J = 6.8 Hz, 2H), 4.51 (t, J = 6.8 Hz, 2H), 3.94 (d, J = 7.6 Hz, 2H), 2.65 (m, 2H), 2.56-2.48 (m, 4H), 2.29 (m, 2H), 1.24 (s, 18H). MS: 499.4 (M+1)⁺. 1/119 ¹H-NMR (400 MHz, CDCl₃) δ: 7.40 (m, 1H), 7.17 (m, 2H), 6.20 (m, 2H), 5.24 (m, 1H), 4.99 (t, J = 6.8 Hz, 2H), 4.58 (m, 2H), 3.70-3.91 (m, 2H), 2.60 (s, 3H), 1.31-1.62 (m, 22H), 0.23-0.98 (m, 9H). MS: 479.6 (M+1)⁺. 1/120 ¹H-NMR (CDCl₃, 300 MHz) δ: 0.67-0.68 (2H, m), 0.87-1.03 (12H, m), 1.33-1.36 (12H, m), 1.56-1.57 (2H, m), 2.59 (3H, s), 3.82-3.84 (2H, d, J = 7.2 Hz), 4.06 (2H, s), 4.57 (2H, t, J = 6.6 Hz), 5.20 (2H, t, J = 6.6Hz), 5.18-5.23 (1H, m), 6.17-6.19 (1H, m), 6.32 (1H, s), 6.50 (1H, s), 6.80 (1H, s). MS: 496.5 (M+1). 1/121 ¹H-NMR (CDCl₃, 300 MHz) δ: 0.65-0.74 (2H, m), 0.97-1.06 (6H, m), 1.29-1.34 (9H, m), 1.53-1.58 (4H, m), 1.96-2.00 (2H, m), 2.06-2.13 (1H, m), 2.61 (3H, s), 3.48-3.56 (2H, m), 3.82 (2H, d, J = 9.9 Hz), 3.99-4.01 (2H, m), 4.11-4.17 (3H, m), 5.58-5.61 (1H, m), 6.26 (1H, s), 6.48 (1H, s), 6.80 (1H, s). MS: 482.5 (M+1). 1/122 ¹H-NMR (CDCl₃, 400 MHz) δ: 0.67-0.69 (2H, m), 0.98-1.02 (3H, m), 1.36 (18H, m), 1.57 (6H, m), 2.60 (3H, s), 3.78-3.80 (2H, d, J = 7.2 Hz), 4.58 (2H, t, J = 6.8 Hz), 4.99 (2H, t, J = 6.8 Hz), 5.21-5.23 (1H, m), 6.19-6.21 (1H, m), 6.32 (1H, s), 7.05 (2H, s). MS: 466.2 (M+1). 1/123 ¹H-NMR (400 MHz, CDCl₃) δ: 8.18 (d, J = 8.4 Hz, 1H), 7.59 (s, 1H), 7.27 (m, 1H), 6.43 (m, 1H), 6.35 (s, 1H), 4.52 (s, 1H), 3.79 (d, J = 7.2 Hz, 2H), 3.49 (d, J = 6.4 Hz, 2H), 3.04 (s, 3H), 2.62 (s, 3H), 1.62 (m, 9H), 1.54 (m, 3H), 1.46 (m, 6H), 1.26 (m, 12H), 0.97 (m, 3H), 0.60 (m, 2H). MS: 637.3 (M+1). 1/124 ¹H-NMR (400 MHz, CDCl₃) δ: 8.18 (d, J = 8.0 Hz, 1H), 7.58 (s, 1H), 7.24 (m, 1H), 6.30 (s, 1H), 6.17 (m, 1H), 4.49 (s, 1H), 3.86-3.72 (m, 6H), 3.45 (m, 2H), 2.62 (s, 3H), 1.53-1.70 (m, 16H), 1.34-1.31 (m, 12H), 0.98 (m, 3H), 0.60 (m, 2H). MS: 602.3 (M+1). 1/125 ¹H-NMR (400 MHz, CDCl₃) δ: 8.17 (d, J = 8.4 Hz, 1H), 7.58 (s, 1H), 7.24 (m, 1H), 6.52 (m, 1H), 6.30 (s, 1H), 6.17 (br s, 1H), 5.28 (br s, 1H), 4.54 (m, 1H), 3.76 (m, 2H), 3.54 (m, 2H), 2.61 (s, 3H), 1.45-1.62 (m, 12H), 1.35-1.31 (m, 18H), 0.98 (m, 3H), 0.60 (m, 2H). MS: 587.4 (M+1)⁺. 1/126 ¹H-NMR (400 MHz, DMSO-d₆) δ: 8.14 (d, J = 8.0 Hz, 1H), 7.85 (m, 1H), 7.82 (s, 1H), 7.52 (s, 1H), 7.42 (m, 1H), 6.64 (s, 1H), 4.60 (m, 2H), 4.32 (t, J = 6.0 Hz, 2H), 3.82 (m, 2H), 3.42 (m, 2H), 3.10 (m, 1H), 2.52 (s, 3H), 1.54 (s, 9H), 1.43 (m, 3H), 1.18 (m, 12H), 0.88 (m, 3H), 0.59 (m, 2H). MS: 558.7 (M+1)⁺. 1/127 ¹H-NMR (400 MHz, DMSO-d₆) δ: 8.17 (d, J = 8.4 Hz, 1H), 7.89 (m, 1H), 7.86 (s, 1H), 7.56 (s, 1H), 7.46 (m, 1H), 6.73 (s, 1H), 4.50 (d, J = 5.6 Hz, 2H), 4.18 (d, J = 5.6 Hz, 2H), 3.87 (m, 2H), 3.39 (m, 2H), 2.58-2.54 (m, 3H), 1.58 (s, 9H), 1.46 (m, 3H), 1.26-1.22 (m, 6H), 1.23 (s, 9H), 0.89 (m, 3H), 0.66 (m, 2H). MS: 572.2 (M+1)⁺. 1/128 ¹H-NMR (400 MHz, DMSO-d₆) δ: 8.13 (d, J = 8.4 Hz, 1H), 7.73 (s, 1H), 7.65 (m, 1H), 7.52 (s, 1H), 7.40 (m, 1H), 6.65 (s, 1H), 4.34 (m, 1H), 3.82 (m, 2H), 3.37 (m, 2H), 3.12 (m, 2H), 2.52 (s, 3H), 1.54 (s, 9H), 1.51-1.38 (m, 7H), 1.31 (m, 2H), 1.22-1.06 (m, 12H), 0.89 (m, 3H), 0.65 (m, 2H). MS: 574.1 (M+1)⁺. 1/129 ¹H-NMR (400 MHz, CDCl₃) δ: 8.16 (d, J = 8.4 Hz, 1H), 7.57 (s, 1H), 7.25 (m, 1H), 6.39 (m, 1H), 6.27 (s, 1H), 4.83 (s, 1H), 3.77 (m, 2H), 3.53 (m, 2H), 2.60 (s, 3H), 1.61 (s, 9H), 1.58 (m, 3H), 1.29 (m, 18H), 0.98 (m, 3H), 0.59 (m, 2H). MS: 588.3 (M+1)⁺. 1/130 ¹H-NMR (400 MHz, DMSO-d₆) δ: 8.12 (d, J = 8.4 Hz, 1H), 7.95 (m, 1H), 7.74 (s, 1H), 7.52 (s, 1H), 7.40 (m, 1H), 6.62 (s, 1H), 3.85 (m, 2H), 3.59 (m, 2H), 3.29 (m, 2H), 3.01 (s, 3H), 2.53 (s, 3H), 1.54 (s, 9H), 1.45 (m, 3H), 1.16 (m, 12H), 0.87 (m, 3H), 0.56 (m, 2H). MS: 594.0 (M+1)⁺. 1/131 ¹H-NMR (400 MHz, DMSO-d₆) δ: 8.14 (d, J = 8.4 Hz, 1H), 7.74 (s, 1H), 7.52 (s, 1H), 7.46 (m, 1H), 7.40 (m, 1H), 6.69 (s, 1H), 4.01-3.81 (m, 5H), 3.35 (m, 2H), 2.52 (s, 3H), 1.71 (m, 2H), 1.60-1.40 (m, 14H), 1.25-1.05 (m, 12H), 0.92-0.81 (m, 3H), 0.59 (m, 2H). MS: 572.1 (M+1)⁺. 1/132 ¹H-NMR (CDCl₃, 300 MHz) δ: 0.68-0.69 (2H, m), 0.85-0.96 (2H, m), 0.99-1.08 (3H, m), 1.20-1.42 (5H, m), 1.59-1.62 (3H, m), 1.94 (2H, t, J = 5.1 Hz), 2.57 (3H, s), 3.65 (2H, d, J = 7.2 Hz), 4.44 (2H, t, J = 5.1 Hz), 4.56 (2H, t, J = 6.9 Hz), 4.98 (2H, t, J = 6.9 Hz), 5.20 (1H, m), 6.14-6.15 (2H, m), 6.73 (1H, d, J = 1.8 Hz), 7.28 (1H, d, J = 1.8 Hz). MS: 503 (M+1)⁺.

A solution of compound of Example 1/14 (96 mg, 0.2 mmol) in DCM (6 mL) was treated with m-chloroperoxybenzoic acid (99 mg, 0.4 mmol) in an ice-bath for 1 h and then allowed to warm to rt and stirred for 3 h. The mixture was quenched with aq. Na₂SO₃ and extracted with EA (3x 30 mL). The organic layer was separated and washed with brine and dried over Na₂SO₄. After filtration, the filtrate was evaporated and purified by prep. HPLC to give the target compound 2 (38 mg, 40%). ¹H-NMR (400 MHz, DMSO-d₆) δ: 8.15 (d, J = 8.0 Hz, 1H), 7.36 (s, 1H), 7.16 (d, J = 1.6 Hz, 2H), 6.53 (s, 1H), 4.40-4.33 (m, 1H), 4.04-3.99 (m, 2H), 3.77 (d, J = 6.8 Hz, 2H), 3.30-3.27 (m, 2H), 2.50 (s, 3H), 1.45-1.38 (m, 3H), 1.31-1.16 (m, 21H), 0.97-0.85 (m, 3H), 0.67-0.57 (m, 2H). MS: 497.1 (M+1).

The following Examples were prepared from the corresponding thioether similar as described in Example 2: # Structure Analytical data 2/1 ¹H-NMR (400 MHz, CDCl₃) δ: 8.19 (d, J = 8.4 Hz, 1H), 7.58 (d, 1H), 7.24 (d, 1H), 6.37-6.34 (m, 2H), 4.74-4.67 (m, 2H), 4.21-4.16 (m, 2H), 3.78 (d, J = 6.8 Hz, 2H), 3.35-3.30 (m, 2H), 2.60 (s, 3H), 1.61 (s, 9H), 1.58-1.53 (m, 3H), 1.34-1.25 (m, 12H), 0.99-0.96 (d, 3H), 0.68-0.60 (m, 2H). MS: 576.0 (M+1). 2/2 ¹H-NMR (400 MHz, CDCl₃) δ: 7.28-7.27 (m, 1H), 7.13 (t, 1H), 7.00 (t, 1H), 6.18 (s, 1H), 6.02 (d, J = 7.2 Hz, 1H), 4.66-4.59 (m, 1H), 4.19-4.13 (m, 2H), 3.72 (d, J = 7.2 Hz, 2H), 3.22-3.16 (m, 2H), 2.59 (s, 3H), 1.53 (m, 3H), 1.42 (m, 3H), 1.41-1.31 (m, 12H), 1.00-0.98 (m, 3H), 0.89-0.86 (m, 2H), 0.77-0.74 (m, 2H), 0.66-0.63 (m, 2H). MS: 595.0 (M+1). 2/3 ¹H-NMR (400 MHz, CDCl₃) δ: 7.31 (s, 1H), 7.10 (s, 1H), 6.31 (s, 1H), 6.26 (d, J = 8.0 Hz, 1H), 4.69-4.63 (m, 1H), 4.19-4.14 (m, 2H), 3.80-3.73 (m, 4H), 3.28-3.22 (m, 2H), 2.60 (s, 3H), 1.66-1.55 (m, 15H), 1.38-1.30 (m, 9H), 1.02-0.98 (m, 3H), 0.65-0.61 (m, 2H). MS: 588.3 (M+1).

To a solution of compound 2 (67 mg, 0.14 mmol) in DCM (2 mL), cooled to 0°C, was added titanium isopropoxide (42 µL, 0.14 mmol) followed by hydrogen peroxide (58 µL, 0.56 mmol) and the solution was stirred at 0°C for 15 min. The ice-bath was removed and stirring was continued at rt for 1 h. The mixture was diluted with DCM (10 mL) and quenched by addition of H₂O (10 mL). The organic layers was separated and washed with brine and dried over Na₂SO₄. After filtration, the filtrate was evaporated and purified by prep. HPLC to give the target compound 3 (40 mg, 56%). ¹H-NMR (400 MHz, DMSO-d₆) δ: 8.20 (d, J = 3.6 Hz, 1H), 7.37 (s, 1H), 7.16 (d, J = 1.6 Hz, 2H), 6.55 (s, 1H), 4.53-4.47 (m, 3H), 4.28-4.23 (m, 2H), 3.77 (d, J = 7.2 Hz, 2H), 2.52 (s, 3H), 1.45-1.43 (m, 3H), 1.31-1.20 (m, 21H), 0.94-0.86 (m, 3H), 0.66-0.61 (m, 2H). MS: 513.3 (M+1).

Compound of Example 1/15 (400 mg, 0.71 mmol) was treated with HCl/CH₃OH (20 mL) at rt for 18 h. The solvent was evaporated to give intermediate 4a (355 mg, 100%) as a colorless solid, which was used without further purification.

To a mixture of compound 4a (100 mg, 0.2 mmol) and DIPEA (78 mg, 0.6 mmol) in DCM (15 mL) was added 2-methoxyacetyl chloride (26 mg, 0.24 mmol) at 0°C and the mixture was stirred for 2 h. Then it was quenched with H₂O (20 mL) and extracted with DCM (3x 20 mL). The organic layer was separated and washed with brine and dried over Na₂SO₄. After filtration, the filtrate was evaporated and purified by prep. HPLC to give the target compound 4 (56 mg, 52%). ¹H-NMR (400 MHz, CDCl₃) δ: 7.38 (t, J = 1.8 Hz, 1H), 7.17 (d, J = 1.6 Hz, 2H), 6.96 (br s, 1H), 6.50 (s, 1H), 4.39 (br s, 2H), 4.04 (s, 1H), 3.96-3.87 (m, 2H), 3.73 (d, J = 7.2 Hz, 2H), 3.66-3.63 (m, 1H), 3.48-3.43 (m, 1H), 3.38 (s, 3H), 2.58 (s, 3H), 1.53-1.49 (m, 3H), 1.37-1.28 (m, 21H), 0.99-0.95 (m, 3H), 0.68-0.61 (m, 2H). MS: 536.2 (M+1).

To a mixture of compound 4a (100 mg, 0.2 mmol) and DIPEA (78 mg, 0.6 mmol) in DCM (15 mL) was added acetyl chloride (19 mg, 0.24 mmol) at 0°C and the mixtures was stirred for 2 h. Then it was quenched with H₂O (20 mL) and extracted with DCM (3x 20 mL). The organic layer was separated and washed with brine and dried over Na₂SO₄. After filtration, the filtrate was evaporated and purified by prep. HPLC to give the target compound 5 (59 mg, 54%). ¹H-NMR (400 MHz, DMSO-d₆) δ: 7.98 (t, J = 5.6 Hz, 1H), 7.36 (t, J = 1.6 Hz, 1H), 7.15 (d, J = 1.6 Hz, 2H), 6.29 (s, 1H), 4.27-4.18 (m, 2H), 3.99-3.96 (m, 1H), 3.79 (d, J = 7.2 Hz, 2H), 3.31-3.27 (m, 1H), 3.10-3.03 (m, 1H), 2.53 (s, 3H), 1.83 (s, 3H), 1.46-1.43 (m, 3H), 1.30 (s, 18H), 1.24-1.15 (m, 3H), 0.97-0.85 (m, 3H), 0.68-0.60 (m, 2H). MS: 506.1 (M+1).

To a mixture of compound P1 (3.0 g, 9.4 mmol), 5-bromo-1-(cyclohexylmethyl)-2-methyl-N-(oxetan-3-yl)-1H-pyrrole-3-carboxamide (similar prepared as in Example 1) (4.3 g, 10.6 mmol), K₂CO₃ (3.12 g, 22.6 mmol) and TBAB (180 mg, 0.54 mmol) in 1,4-dioxane (10 mL) and H₂O (4 mL) was added Ph(PPh₃)₂Cl₂ (180 mg, 0.24 mmol) under N₂. Under microwave conditions, the solution was heated at 100°C for 1.5 h. Water was added and the solution was extracted with EA. The organic layer was washed with brine, dried over NaSO₄, filtered, concentrated and purified by CC (PE/EA = 3/1) to give compound 6a (1.8 g, 41%) as a colorless solid.

To a stirred solution of compound 6a (1.65 g, 3.54 mmol) in a mixture of THF (15 mL) and H₂O (5 mL) was added LiOH•H₂O (300 mg, 5.64 mmol) and this mixture was stirred at 60°C for 3 h. The solution was adjusted to pH = 2-3 with 1M HCl. Then the mixture was extracted with EA. The organic layer was washed with brine, dried over Na₂SO₄, concentrated and purified by CC (PE/EA = 2/1) to give compound 6b (1.3 g, 81%) as a colorless powder.

A mixture of compound 6b (150 mg, 0.33 mmol), tert-butylamine (36 mg, 0.48 mmol), HATU (207 mg, 0.54 mmol) and DIPEA (146 mg, 1.14 mmol) in DMF (5 mL) was stirred at rt for 20 min. The mixture was washed with water and extracted with EA. The organic layer was washed with brine, dried over Na₂SO₄, concentrated and purified by CC (PE/EA = 2/1) to give compound 6 (42 mg, 30%) as a colorless powder. ¹H-NMR (CDCl₃, 300 MHz) δ: 8.19 (s, 1H), 7.94 (s, 1H), 7.39 (s, 1H), 6.45 (s, 1H), 6.38 (d, J = 6.9 Hz, 1H), 5.20 (q, J = 6.9 Hz, 1H), 4.97 (t, J = 6.9 Hz, 2H), 4.60 (t, J = 6.9 Hz, 2H), 3.84 (d, J = 6.9 Hz, 2H), 2.60 (s, 3H), 1.66 (m, 2H), 1.51 (s, 9H), 1.40 (s, 9H), 1.38-1.29 (m, 3H), 1.03-0.97 (m, 3H), 0.68-0.61 (m, 2H). MS: 509 (M+1).

The following Examples were prepared similar as in Example 6: # Structure Analytical data 6/1 ¹H-NMR (CDCl₃, 300 MHz) δ: 7.33 (s, 1H), 7.26 (s, 1H), 6.42 (s, 1H), 6.33 (d, J = 6.9 Hz, 1H), 5.20 (q, J = 6.9 Hz, 1H), 4.96 (t, J = 6.9 Hz, 2H), 4.58 (t, J = 6.9 Hz, 2H), 3.84 (d, J = 6.9 Hz, 2H), 2.92 (s, 3H), 2.59 (s, 3H), 1.73-1.62 (m, 2H), 1.53 (s, 9H), 1.43 (s, 9H), 1.38-1.30 (m, 4H), 1.03-0.97 (m, 3H), 0.72-0.63 (m, 2H).MS: 523 (M+1). 6/2 ¹H-NMR (CDCl₃, 400 MHz) δ: 7.44 (d, 1H, J = 1.6 Hz), 7.25 (d, 1H, J = 8.0 Hz), 7.16 (dd, 1H, J = 8.0 Hz, 1.6 Hz), 6.17 (s, 1H), 6.09-6.07 (m, 1H), 5.60 (d, 1H, J = 8.0 Hz), 4.18-4.09 (m, 3H), 3.99-3.96 (m, 2H), 3.75 (d, 2H, J = 7.2 Hz), 3.55-3.49 (m, 2H), 3.29 (t, 2H, J = 6.4 Hz), 2.62 (s, 3H), 2.00-1.96 (m, 2H), 1.58-1.47 (m, 5H), 1.44 (s, 9H), 1.41-1.33 (m, 3H), 1.06-1.00 (m, 3H), 0.67-0.62 (m, 2H). MS: 562 (M+1). 6/3 ¹H-NMR (CDCl₃, 400 MHz) δ: 7.43 (d, 1H, J = 1.6 Hz), 7.33 (d, 1H, J = 7.6 Hz), 7.16 (dd, 1H, J = 7.6 Hz, 1.6 Hz), 6.17 (s, 1H), 5.75 (m, 2H), 5.60 (t, 2H, J = 7.2 Hz), 4.19-4.14 (m, 1H), 3.99-3.96 (m, 2H), 3.75 (d, 2H, J = 7.6 Hz), 3.55-3.48 (m, 2H), 2.61 (s, 3H), 2.04-1.96 (m, 5H), 1.54-1.46 (m, 5H), 1.44 (s, 9H), 1.41-1.36 (m, 3H), 1.03-1.05 (m, 3H), 0.67-0.62 (m, 2H). MS: 480 (M+1). 6/4 ¹H-NMR (CDCl₃, 400 MHz) δ: 7.40 (d, 1H, J = 1.2 Hz), 7.24 (d, 1H, J = 7.6 Hz), 7.13 (dd, 1H, J = 8.0 Hz, 1.2 Hz), 6.15 (s, 1H), 5.74 (d, 1H, J = 4.8 Hz), 5.60 (d, 1H, J = 7.2 Hz), 4.18-4.15 (m, 1H), 3.99-3.96 (m, 2H), 3.75 (d, 2H, J = 7.2 Hz), 3.55-3.49 (m, 2H), 3.01-3.00 (d, 3H, J = 4.8 Hz), 2.61 (s, 3H), 1.56-1.53 (m, 5H), 1.47 (s, 9H), 1.41-1.36 (m, 3H), 1.01-0.99 (m, 3H), 0.62-0.87 (m, 2H). MS: 494 (M+1). 6/5 ¹H-NMR (CDCl₃, 400 MHz) δ: 7.43 (d, 1H, J = 1.6 Hz), 7.24 (dd, 1H, J = 8.0 Hz, 1.6 Hz), 7.08 (d, 1H, J = 8.0 Hz), 6.18 (s, 1H), 5.61 (t, 2H, J = 7.2 Hz), 4.18-4.14 (m, 1H), 3.99-3.96 (m, 2H), 3.75 (d, 2H, J = 8.0 Hz), 3.55-3.49 (m, 2H), 3.12 (s, 3H), 2.82 (s, 3H), 2.61 (s, 3H), 1.99-1.96 (m, 2H), 1.53-1.48 (m, 5H), 1.42-1.23 (m, 12H), 1.01-1.00 (m, 3H), 0.64-0.61 (m, 2H). MS: 508 (M+1). 6/6 ¹H-NMR (CDCl₃, 400 MHz) δ: 7.40 (d, 1H, J = 1.2 Hz), 7.22 (d, 1H, J = 8.0 Hz), 7.13 (dd, 1H, J = 8.0 Hz, 1.2 Hz), 6.14 (s, 1H), 5.60 (t, 2H, J = 7.2 Hz), 4.18-4.14 (m, 1H), 4.00-3.96 (m, 3H), 3.73 (d, 2H, J = 7.2 Hz), 3.55-3.48 (m, 2H), 2.61 (s, 3H), 2.09-1.96 (m, 5H), 1.78-1.74 (m, 2H), 1.68-1.65 (m, 1H), 1.56-1.53 (m, 4H), 1.51-1.43 (m, 12H), 1.41-1.36 (m, 3H), 1.29-1.19 (m, 4H), 1.03-1.05 (m, 3H), 0.66-0.69 (m, 2H). MS: 562 (M+1). 6/7 ¹H-NMR (CDCl₃, 400 MHz) δ: 7.41 (d, 1H, J = 1.6 Hz), 7.25 (d, 1H, J = 8.0 Hz), 7.14 (dd, 1H, J = 8.0 Hz, 1.6 Hz), 6.15 (s, 1H), 5.79 (t, 2H, J = 6.0 Hz), 5.60 (d, 1H, J = 8.0 Hz), 4.18-4.15 (m, 1H), 4.00-3.95 (m, 2H), 3.75 (d, 2H, J = 7.6 Hz), 3.55-3.49 (m, 2H), 3.29 (t, 2H, J = 6.4 Hz), 2.61 (s, 3H), 2.00-1.96 (m, 2H), 1.82-1.74 (m, 4H), 1.71-1.67 (m, 4H), 1.51-1.43 (m, 12H), 1.41-1.32 (m, 6H), 1.19-1.05 (m, 5H), 0.66-0.69 (m, 2H). MS: 576 (M+1). 6/8 ¹H-NMR (400 MHz, DMSO-d₆) δ: 8.14 (s, 1H), 7.80-7.67 (m, 2H), 7.55-49 (m, 2H), 6.72 (s, 1H), 4.01-3.82 (m, 5H), 3.35 (m, 2H), 2.55 (s, 3H), 1.75-1.67 (m, 2H), 1.59-1.44 (m, 5H), 1.36 (s, 9H), 1.34-1.24 (m, 3H), 0.98 (m, 3H), 0.63 (m, 2H). MS: 548.3 (M+1)⁺. 6/9 ¹H-NMR (400 MHz, DMSO-d₆): δ 8.41 (d, J = 8.0 Hz, 1H), 7.80-7.67 (m, 2 H), 7.52 (d, J = 8.0 Hz, 2H), 6.73 (s, 1H), 3.99-3.83 (m, 5H), 3.72 (m, 1H), 3.40-3.32 (m, 2H), 2.55 (s, 3H), 1.86-1.80 (m, 2H), 1.76-1.67 (m, 4H), 1.62-1.47 (m, 6H), 1.40-1.10 (m, 8H), 0.98 (s, 3H), 0.65 (m, 2H). MS: 574.3 (M+1)⁺.

To a solution of ethyl 2-methyl-1H-pyrrole-3-carboxylate (1.0 g, 6.52 mmol) in dry DMF (10 mL) was added NaH (172 mg, 7.17 mmol) in portions and the resulting mixture was stirred at rt for 30 min. A solution of piperidine-1-sulfonyl chloride (1.32 g, 7.17 mmol) in dry DMF (4 mL) was added and the resulting mixture was stirred at rt for 3 h. The mixture was quenched with aq. NH₄Cl and diluted with EA. The organic phase was washed with water and brine and dried over Na₂SO₄. After filtration the organic phase was concentrated and purified by CC (PE/EA = 10/1) to give 7a as a colorless solid (1.7 g).

To a solution of compound 7a (600 mg, 2 mmol) in dry DMF (8 mL) was added NBS (409 mg, 2.3 mmol) in portions at 0°C and this mixture was stirred at rt for 3 h. The mixture was diluted with EA and washed with water and brine. The organic phase was dried over Na₂SO₄, concentrated and purified by CC (PE/EA = 15/1) to give compound 7b (700 mg) as a pale-yellow solid.

A mixture of compound 7b (700 mg, 1.85 mmol), 2-(3,5-di-tert-butylphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (519 mg, 2.22 mmol) and Pd(PPh₃)₄ (107 mg) in degassed 1,2-dimethoxyethane (5 mL) and 2M Na₂CO₃ (8 mL) was heated to 100°C for 30 min under microwave irradiation. The mixture was cooled and diluted with EA and washed with water and brine. The organic phase was dried over Na₂SO₄, concentrated and purified by CC (PE/EA = 100/1 to 80/1) to give compound 7c as a colorless solid (500 mg).

A mixture of compound 7c (300 mg, 0.614 mmol), LiOH·H₂O (503 mg, 12.3 mmol) and NaOH (125 mg) in 1,4-dioxane (5 mL) and water (3 mL) was stirred and heated to 120°C for 25 min under microwave irradiation. The mixture was cooled and acidified by 2M HCl to pH∼2 and then extracted with EA. The combined extracts were washed with water and brine, dried over Na₂SO₄, concentrated and purified by CC (PE/EA = 10/1 to 2/1) to give compound 7d (250 mg) as a colorless solid.

To a solution of compound 7d (100 mg, 217 µmol), oxetan-3-amine (18 mg, 238 µmol) and HATU (124 mg, 326 µmol) in dry DMF (2 mL) at 0°C was added DIPEA (42 mg, 326 µmol) and the resulting mixture was stirred at rt overnight. The mixture was diluted with water, extracted with EA and the combined extracts were washed with water and brine. The organic phase was dried over Na₂SO₄, concentrated and purified by CC (PE/EA = 3/1 to 2/1) to give compound 7 (80 mg, 72%) as a colorless solid. ¹H-NMR (400 MHz, CDCl₃) δ: 7.41 (1H, s), 7.28 (2H, s), 6.22 (1H, s), 6.19 (1H, d, J = 7.2 Hz), 5.23-5.17 (1H, m), 4.99 (2H, t, J = 6.8 Hz), 4.55 (2H, t, J = 6.4 Hz), 2.81 (3H, s), 2.74 (4H, m), 1.34 (23H, m), 0.85 (1H, m). MS: 516.4 (M+1)⁺.

The following Examples were prepared similar as in Example 7: # Structure Analytical data 7/1 ¹H-NMR (400 MHz, CDCl₃) δ: 7.41 (1H, s), 7.26 (2H, s), 6.22 (1H, s), 6.20 (1H, d, J = 8.0 Hz), 5.21-5.18 (1H, m), 4.99 (2H, t, J = 7.2 Hz), 4.55 (2H, t, J = 6.4 Hz), 3.28 (2 H, m), 2.81 (3H, s), 2.20 (2H, m), 1.42 (2H, m), 1.34 (18H, s), 1.23 (1H, m), 0.95 (2H, m), 0.83 (3H, d, J = 6.8 Hz). MS: 530.3 (M+1)⁺. 7/2 ¹H-NMR (400 MHz, CDCl₃) δ: 7.42 (1H, s), 7.28 (2H, m), 6.22 (1H, s), 6.19 (1H, m), 5.21-5.17 (1H, m), 4.99 (2H, t, J = 6.8 Hz), 4.55 (2H, t, J = 6.4 Hz), 3.23 (1H, m), 3.14 (1H, m), 2.81 (3H, s), 2.15 (1H, m), 1.68 (1H, m), 1.61-1.57 (1H, m), 1.50-1.45 (1H, m), 1.34 (20H, s), 0.90 (1H, m), 0.69 (3H, d, J = 6.4 Hz). MS: 530.3 (M+1)⁺. 7/3 ¹H-NMR (400 MHz, DMSO-d₆) δ: 8.53 (1H, d, J = 6.4 Hz), 7.42 (1H, s), 7.24 (2H, s), 6.56 (1H, s), 4.98-4.92 (1H, m), 4.72 (1H, t, J = 6.8 Hz), 4.53 (1H, t, J = 6.4 Hz), 3.13 (2H, m), 2.71 (3H, s), 1.68-1.49 (3H, m), 1.34-1.20 (19H, m), 0.68 (6H, m), 0.40-0.36 (1H, m). MS: 544.4 (M+1)⁺. 7/4 ¹H-NMR (400 MHz, DMSO-d₆) δ: 8.50 (1H, d, J = 6.4 Hz), 7.41 (1H, s), 7.21 (2H, s), 6.63 (1H, s), 4.95-4.91 (1H, m), 4.72 (1H, t, J = 6.8 Hz), 4.52 (1H, t, J = 6.4 Hz), 2.71-2.69 (7H, m), 1.40 (8H, s), 1.34 (18H, s). MS: 530.3 (M+1)⁺. 7/5 ¹H-NMR (400 MHz,DMSO-d₆) δ: 8.53 (1H, d, J = 6.4 Hz), 7.41 (1H, s), 7.23 (2H, s), 6.65 (1H, s), 4.98-4.92 (1H, m), 4.73 (1H, t, J = 6.4 Hz), 4.53 (1H, t, J = 6.4 Hz), 3.11 (1H, m), 2.71 (3H, s), 2.36 (3H, s), 1.63 (2H, m), 1.48 (1H, m), 1.32 (18H, s), 1.27-0.95 (5H, m). MS: 544.4 (M+1)⁺. 7/6 ¹H-NMR (400 MHz, CDCl₃) δ: 8.52 (1H, d, J = 6.8 Hz), 7.42 (1H, s), 7.25 (2H, s), 6.66 (1H, s), 4.94 (1H, m), 4.72 (2H, t, J = 6.8 Hz), 4.53 (2H, t, J = 6.4 Hz), 2.93 (2H, t, J = 6.8 Hz), 2.71 (3H, s), 2.62 (2H, s), 1.52-1.40 (6H, m), 1.31 (22H, m). MS: 556.5 (M+1)⁺. 7/7 ¹H-NMR (400 MHz, DMSO-d₆): δ 7.75 (1H, t, J = 6.4 Hz), 7.39 (1H, s), 7.24 (2H, s), 6.62 (1H, s), 4.50 (1H, br s), 3.17 (2H, d, J = 6.0 Hz), 2.77-2.68 (7H, m), 1.30 (19H, m), 1.21 (5H, m), 1.07 (6H, s). MS: 532.4 (M+1)⁺. 7/8 ¹H-NMR (400 MHz,CDCl₃): δ 7.41 (s, 1H), 7.28 (s, 2H), 6.22 (s, 1H), 5.59 (br, s, 2H), 2.84 (s, 3H), 2.76-2.73 (m, 4H), 1.34 (s, 18H), 1.26 (m, 6H). MS: 460.2 (M+1)⁺.

To a stirred solution of ethyl 1-(cyclohexylmethyl)-2-methyl-1H-pyrrole-3-carboxylate (8.0 g, 32.1 mmol, prepared according to Example 1d) and 1-methylvinyl acetate (6.4 g, 64.2 mmol) in 1,2-dichloroethane (100 mL) was added p-toluenesulfonic acid monohydrate (250 mg, 1.45 mmol) under N₂ and the mixture was stirred and heated to reflux overnight. After cooling rt the mixture was diluted with water and extracted with DCM twice. The combined organic layers were dried over Na₂SO₄, filtered, concentrated and purified by CC (PE/EA = 30/1) to give compound 8a (5.7 g, 61%) as a yellow solid.

To a solution of compound 8a (5.4 g, 18.5 mmol) and picolinaldehyde (4.0 g, 37.4 mmol) in THF (60 mL) was added DBU (3.1 g, 20.4 mmol) and the solution was stirred at rt for 3 d. The solution was quenched with aq. NH₄Cl and extracted with EA twice. The combined organic layers were washed with brine and dried over Na₂SO₄, filtered, concentrated and purified by CC (PE/EA = 20/1) to give compound 8b (3.8 g, 54%) as a yellow solid.

To a solution of compound 8b (3.7 g, 9.7 mmol) in MeOH (100 mL) was added Pd/C (370 mg) and the mixture was stirred at rt under H₂ (15 psi) overnight. The solution was filtered, concentrated and purified by CC (PE/EA = 20/1) to give compound 8c (3.2 g, 86%) as a colorless solid.

A solution of compound 8c (3.0 g, 7.8 mmol) in dry toluene (50 mL) was refluxed with a Dean-Stark tube to remove water under N₂ for 10 min and then (methoxycarbonyl-sulfamoyl)triethylammonium hydroxide inner salt (Burgess reagent, 3.8 g, 15.9 mmol) was added to the mixture. The mixture was heated to reflux for further 30 min and cooled to rt. The solution was quenched with aq. NH₄Cl and extracted with EA twice. The combined organic layers were washed with brine and dried over Na₂SO₄, filtered, concentrated and purified by CC (PE/EA = 3/1) to give compound 8d (2.1 g) as a yellow solid.

To a solution of compound 8d (700 mg, 1.4 mmol) in ACN (20 mL) was added 1,5-dibromopentane (383 mg, 1.68 mmol) and K₂CO₃ (483 mg, 3.5 mmol) and the mixture was stirred overnight at reflux. The resulting solution was cooled to rt and further K₂CO₃ (483 mg, 3.5 mmol) was added. The solution was stirred again overnight at reflux. After cooling to rt the mixture was diluted with water and extracted with EA twice. The combined organic layers were washed brine, dried over Na₂SO₄, filtered and concentrated to dryness. CC (PE/EA = 10/1) afforded compound 8e (610 mg, 85%) as an oil.

To a stirred solution of compound 8e (600 mg, 1.17 mmol) in a mixture of DMSO (15 mL) and H₂O (2 drops) was added KOtBu (655 mg, 5.85 mmol) and the mixture was stirred at 85°C for 4 h. After cooling to rt the pH was adjusted to pH 2-3 with 1M HCl and then the mixture was extracted with EA. The organic layer was washed with water and brine, dried over Na₂SO₄, concentrated and purified by CC (PE/EA = 2/1) to give compound 8f (450 mg, 80%) as a yellow solid.

A mixture of compound 8f (150 mg, 0.31 mmol), (3-methyloxetan-3-yl)methanamine (62 mg, 0.62 mmol), HATU (207 mg, 0.54 mmol) and DIPEA (146 mg, 1.14 mmol) in DMF (5 mL) was stirred at rt for 20 min. The resulting solution was diluted with water and extracted with EA twice. The combined organic layers were washed with water three times and brine consecutively, dried over Na₂SO₄, concentrated and purified by prep. TLC (PE/EA = 1/1) to give compound 8 (30 mg, 16%) as a pale yellow powder. ¹H-NMR (CDCl₃, 400 MHz) δ: 8.05 (d, 1H, J = 9.2 Hz), 7.81 (d, 1H, J = 6.8 Hz), 7.10-7.05 (m, 2H), 6.77-6.73 (m, 1H), 6.47 (s, 1H), 6.10 (t, 1H, J = 6.0 Hz), 4.55 (d, 2H, J = 6.0 Hz), 4.42 (d, 2H, J = 6.0 Hz), 3.56 (d, 2H, J = 6.0 Hz), 3.52 (d, 2H, J = 7.2 Hz), 3.00 (m, 4H), 2.64 (s, 3H), 1.67-1.62 (m, 4H), 1.57-1.53 (m, 5H), 1.37-1.25 (m, 6H), 0.99-0.95 (m, 3H), 0.61-0.57 (m, 2H). MS: 567.1 (M+1)⁺.

The following Examples were prepared similar as in Example 8: # Structure Analytical data 8/1 ¹H-NMR (CDCl₃, 400 MHz) δ: 8.06 (d, 1H, J = 8.8 Hz), 7.82 (d, 1H, J = 6.8 Hz), 7.10-7.05 (m, 2H), 6.77-6.73 (m, 1H), 6.48 (s, 1H), 6.20 (m, 1H), 3.52 (d, 2H, J = 7.2 Hz), 3.41 (d, 2H, J = 6.0 Hz), 3.00 (m, 4H), 2.63 (s, 3H), 1.67-1.63 (m, 4H), 1.60-1.53 (m, 3H), 1.44-1.37 (m, 15H), 0.99-0.95 (m, 3H), 0.61-0.57 (m, 2H). MS: 555.1 (M+1)⁺. 8/2 ¹H-NMR (CDCl₃, 400 MHz) δ: 8.06 (d, 1H, J = 8.8 Hz), 7.82 (d, 1H, J = 6.8 Hz), 7.11-7.06 (m, 2H), 6.76 (t, 1H, J = 5.4 Hz), 6.49 (s, 1H), 6.22 (d, 1H, J = 7.2 Hz), 5.24-5.19 (m, 1H), 5.00 (t, 1H, J = 7.2 Hz), 4.57 (t, 1H, J = 7.2 Hz), 3.52 (d, 2H, J = 7.2 Hz), 3.00 (m, 4H), 2.62 (s, 3H), 1.67-1.52 (m, 9H), 1.39-1.24 (m, 4H), 0.99-0.95 (m, 3H), 0.61-0.57 (m, 2H). MS: 539.1 (M+1)⁺.

To a solution of 1-(cyclohexylmethyl)-2-ethyl-1H-pyrrole-3-carboxylate (prepared according to Example 1d, 875 mg, 3.5 mmol) in EtOH (50 mL) was added 5M KOH (10 mL). The mixture was stirred and heated to reflux overnight. After cooling to rt the solvent was concentrated and the pH of the remaining aq. mixture was adjusted to <2 with 4M HCl. The mixture was extracted with EA three times and the combined organic layers were washed with brine and dried over Na₂SO₄. After filtration, the filtrate was evaporated and purified by prep. HPLC to give pure product 9a as a colorless solid.

To a solution of 9a (505 mg, 2.29 mmol) in DMF (15 mL) was added HATU (1.74 mg, 4.58 mmol) and DIPEA (1.48 mg, 11.5 mmol). The mixture was stirred for 60 min and then oxetan-3-amine (185 mg, 2.52 mmol) was added. The mixture was stirred for additional 18 h, quenched with ice water and extracted with EA. The organic layer was separated, washed with brine and dried over Na₂SO₄. After filtration, the filtrate was evaporated and purified by prep. HPLC to give 9b (398 mg, 63%) as a colorless solid.

To a solution of 9b (555 mg, 2 mmol) in dry THF (10 mL) was added NBS (374 mg, 2.1 mmol) at -78°C under N₂. The mixture was stirred for 5 min and quenched with a cold aq. solution of NH₄Cl. The organic layer was separated and the aq. layer extracted repeatedly with EA. The combined organic layers were washed with brine and dried over Na₂SO₄. After filtration, the filtrate was evaporated and purified by CC (EA/PE = 1/60) to give compound 9c (630 mg, 89%).

Compound 9c (86 mg, 244 µmol), compound P12 (100 mg, 244 µmol) and Cs₂CO₃ (238 mg, 732 µmol) in 1,4-dioxane/water (10:1, 2.2 mL) were stirred at rt. Pd(PPh₃)₄ (0.03 eq) was added under N₂ and the mixture was stirred and heated under microwave irradiation to 120°C for 2 h. The mixture was cooled to rt, filtered and purified by prep. HPLC to give target 9 (81.5 mg, 60%) as a colorless solid. ¹H-NMR (400 MHz, DMSO-d₆) δ: 8.32-8.30 (d, J = 6.4 Hz, 1H), 7.69 (m, 2H), 7.54-7.53 (t, J = 1.4 Hz, 1H), 6.75 (s, 1H), 4.96 (m, 1H), 4.74-4.70 (t, J = 7.0 Hz, 1H), 4.57-4.53 (t, J = 6.2 Hz, 1H), 3.85-3.82 (m, 1H), 2.97 (s, 3H), 2.53 (s, 3H), 1.48-1.45 (m, 3H), 1.35 (s, 9H), 1.24-1.20 (m, 12H), 0.92 (m, 3H), 0.61 (m, 2H). MS: 558.3 (M+1)⁺.

The following Examples were prepared similar as in Example 9, using the corresponding borononic ester building blocks prepared as or similar as described above: # Structure Analytical data 9/1 ¹H-NMR (400 MHz, DMSO-d₆) δ: 8.33 (d, J = 6.8 Hz, 1H), 7.96 (d, J = 8.4 Hz, 1H), 7.51 (s, 1H), 7.76 (s, 1H), 7.65 (d, J = 7.6 Hz, 1H), 7.42 (d, J = 3.8 Hz, 1H), 7.36 (d, J = 7.2 Hz, 1H), 4.98 (d, J = 6.8 Hz, 1H), 4.75-4.71 (t, J = 7.0 Hz, 2H), 4.58-4.54 (t, J = 6.6 Hz, 2H), 3.85 (d, J = 7.2 Hz, 2H), 3.19-3.16 (m, 4H), 2.54 (s, 3H), 1.46 (s, 7H), 1.35 (m, 5H), 0.92 (d, J = 5.2 Hz, 3H), 0.64-0.60 (t, J = 6.6 Hz, 2H). MS: 539.2 (M+1)⁺. 9/2 ¹H-NMR (400 MHz, DMSO-d₆) δ: 7.95 (d, J = 8.0 Hz, 1H), 7.75 (s, 1H), 7.63-7.61 (m, 1H), 7.56 (s, 1H), 7.41-7.39 (m, 1H), 7.35-7.33 (m, 1H), 6.73 (s, 1H), 3.84-3.82 (d, J = 7.6 Hz, 2H), 3.59 (br s, 1H), 3.19-3.17 (m, 6H), 2.56 (s, 3H), 1.46 (s, 7H), 1.35 (m, 5H), 1.08 (s, 6H), 0.91 (m, 3H), 0.64-0.61 (m, 2H). MS: 555.1 (M+1)⁺. 9/3 ¹H-NMR (400 MHz, DMSO-d₆) δ: 7.68 (m, 2H), 7.55 (m, 2H), 6.69 (s, 1H), 3.99 (s, 1H), 3.84-3.82 (d, J = 6.8 Hz, 2H), 3.17-3.16 (d, J = 6.0 Hz, 2H), 2.96 (s, 3H), 2.54 (s, 3H), 1.48-1.46 (m, 3H), 1.34 (s, 9H), 1.24 (s, 12H), 1.08 (s, 6H), 0.93 (m, 3H), 0.62 (m, 2H). MS: 574.2 (M+1)⁺. 9/4 ¹H-NMR (400 MHz, DMSO-d₆) δ: 8.36 (d, J=6.4Hz, 1H), 8.22 (d, J=8.4Hz, 1H), 7.84 (s, 1H), 7.61 (s, 1H), 7.51 (m, 1H), 6.83 (s, 1H), 5.03 (m, 1H), 4.79 (m, 2H), 4.61 (m, 2H), 3.90 (m, 2H), 2.58 (s, 3H), 1.62 (s, 9H), 1.50 (m, 3H), 1.30-1-20 (m, 12H), 0.95 (m, 3H), 0.67 (m, 2H). MS: 544.2 (M+1)⁺. 9/5 ¹H-NMR (400 MHz, DMSO-d₆) δ: 8.31 (d, J=7.2Htz, 1H), 7.79 (d, J=8.4Hz, 1H), 7.57 (s, 1H), 7.43 (m, 1H), 6.76 (s, 1H), 4.98 (m, 1H), 4.73 (m, 2H), 4.56 (m, 2H), 3.84 (m, 2H), 3.09 (s, 3H), 2.51 (s, 3H), 1.54 (s, 9H), 1.43 (m, 3H), 1.21 (s, 9H), 0.91 (m, 3H), 0.89 (m, 3H), 0.61 (m, 2H). MS: 558 (M+1)⁺. 9/6 ¹H-NMR (400 MHz, DMSO-d₆) δ: 8.31 (d, J=6.4Hz, 1H), 7.81 (d, J=8.0Hz, 1H), 7.58 (s, 1H), 7.43 (m, 1H), 6.76 (s, 1H), 4.96 (m, 1H), 4.72 (m, 2H), 4.54 (m, 2H), 3.83 (d, 2H), 3.59 (m, 2H), 2.51 (s, 3H), 1.55 (s, 9H), 1.43 (m, 3H), 1.27 (m, 12H), 1.18 (m, 3H), 0.88 (m, 3H), 0.60 (m, 2H). MS: 572.3 (M+1)⁺. 9/7 ¹H-NMR (400 MHz, DMSO-d₆) δ: 8.30 (d, J=6.4Hz, 1H), 8.17 (d, J=8.0Hz, 1H), 7.62 (s, 1H), 7.54 (s, 1H), 7.42 (m, 1H), 6.77 (s, 1H), 4.97 (m, 1H), 4.74 (m, 2H), 4.55 (m, 2H), 3.84 (d, 2H), 2.52 (s, 3H), 1.55 (m, 11H), 1.44 (m, 3H), 1.19 (d, 3H), 1.08 (s, 6H), 0.89 (m, 6H), 0.63 (m, 2H). MS: 558.3 (M+1)⁺. 9/8 ¹H-NMR (400 MHz, DMSO-d₆) δ: 8.14 (d, J=8.4Hz, 1H), 7.75 (s, 1H), 7.55-7.45 (m, 2H), 7.42 (m, 1H), 6.71 (s, 1H), 4.61 (s, 1H), 3.85 (m, 2H), 3.15 (m, 2H), 2.52 (s, 3H), 1.54 (s, 9H), 1.45-1.40 (m, 3H), 1.20-1.06 (m, 12H), 1.07 (s, 6H), 0.92-0.80 (m, 3H), 0.56 (m, 2H). MS: 560.3 (M+1)⁺. 9/9 ¹H-NMR (400 MHz, DMSO-d₆) δ: 7.78 (d, J=8.4Hz, 1H), 7.60-7.45 (m, 2H), 7.41 (m, 1H), 6.71 (s, 1H), 4.61 (s, 1H), 3.84 (m, 2H), 3.17 (m, 2H), 3.08 (s, 3H), 2.53 (s, 3H), 1.54 (s, 9H), 1.46-1.40 (m, 3H), 1.22 (s, 9H), 1.27-1.18 (m, 3H), 1.04 (s, 6H), 0.93-0.80 (m, 3H), 0.62 (m, 2H). MS: 574.3 (M+1)⁺. 9/10 ¹H-NMR (400 MHz, DMSO-d₆) δ: 7.80 (d, J=8.4Hz, 1H), 7.62-7.44 (m, 2H), 7.41 (m, 1H), 6.71 (s, 1H), 4.61 (s, 1H), 3.84 (m, 2H), 3.62 (m, 2H), 3.15 (m, 2H), 2.52 (s, 3H), 1.54 (s, 9H), 1.45-1.41 (m, 3H), 1.35-1.16 (m, 15H), 1.07 (s, 6H), 0.96-0.80 (m, 3H), 0.63 (m, 2H). MS: 588.3 (M+1)⁺. 9/11 ¹H-NMR (400 MHz, DMSO-d₆) δ: 8.14 (d, J=8.4Hz, 1H), 7.62 (s, 1H), 7.54-7.50 (m, 2H), 7.42 (m, 1H), 6.72 (s, 1H), 4.61 (s, 1H), 3.86 (m, 2H), 3.18 (m, 2H), 2.53 (s, 3H), 1.560-1.50 (m, 11H), 1.49-1.40 (m, 3H), 1.25-1.21 (m, 3H), 1.08 (s, 12H), 0.93-0.81 (s, 6H), 0.61 (m, 2H). MS: 574.1 (M+1)⁺. 9/12 ¹H-NMR (400 MHz, CDCl₃) δ: 0.68-0.71 (2H, m), 1.01-1.07 (12H, m), 1.37-1.45 (3H, m), 1.58 (3H, m), 2.58 (3H, s), 3.41 (2H, d, J = 5.6 Hz), 3.65 (2H, d, J = 7.2 Hz), 4.57 (2H, t, J = 6.4 Hz), 4.97-5.00 (2H, t, J = 6.4 Hz), 5.04 (1H, s), 5.20-5.22 (1H, m), 6.17 (2H, d, J = 7.6 Hz), 6.20 (1H, s), 7.58 (1H, d, J = 2.4 Hz), 8.20 (1H, d, J = 2.0 Hz). MS: 507.1 (M+1)⁺. 9/13 ¹H-NMR (400 MHz, DMSO-d₆) δ: 0.67-0.69 (2H, m), 0.86-1.02 (12H, m), 1.29-1.36 (3H, m), 1.51-1.53 (3H, m), 2.45 (3H, s), 3.76 (2H, m), 4.12 (2H, s), 4.54 (2H, m), 4.72 (2H, m), 4.94 (1H, m), 6.72 (1H, s), 8.07 (1H, m), 8.28 (1H, m), 8.45 (1H, m). MS: 508.1 (M+1)⁺. 9/14 ¹H-NMR (400 MHz, DMSO-d₆) δ: 8.24 (m, 1H), 8.03 (m, 1H), 7.92 (m, 1H), 6.64 (s, 1H), 4.94 (m, 1H), 4.71 (m, 2H), 4.53 (m, 2H), 3.94 (s, 2H), 3.71 (m, 2H), 2.49 (s, 3H, partial overlay with solvent signal), 1.59-1.52 (m, 2H), 1.50-1.25 (m, 4H), 1.10-1.00 (m, 2H), 0.94 (s, 9H), 0.76 (m, 2H); MS: 508.1 (M+1)⁺. 9/15 ¹H-NMR (300 MHz, CDCl₃) δ: 7.45-7.42 (m, 2H), 6.43 (s, 1H), 6.35 (d, 1H, J = 6.9 Hz), 5.20 (m, 1H), 4.99 (t, 2H, J = 6.9 Hz), 4.58 (t, 2H, J = 6.9 Hz), 3.84 (d, 2H, J = 6.9 Hz), 2.61 (s, 3H), 1.66 (m, 3H), 1.41 (s, 9H), 1.30-1.38 (m, 3H), 0.97-1.03 (m, 3H), 0.63 (m, 2H). MS: 478.2 (M+1).

A solution of ethyl indolizine-1-carboxylate (1.3 g, 6.88 mmol, prepared according J. Org. Chem. 1999, 64:7618) and 10% aq. NaOH (120 mL) in THF (10 mL) was heated to 50°C overnight. The resulting solution was concentrated and adjusted to pH 1 by conc. HCl. The solution was extracted twice with EA. The combined organic layers were washed with brine, dried with Na₂SO₄, filtered and concentrated to give intermediate 10a (0.50 g, 45%) as a colorless solid.

A solution of intermediate 10a (500 mg, 3.11 mmol), HATU (1.42 g, 3.73 mmol) and DIPEA (1.2 g, 9.33 mmol) in DMF (10 mL) was stirred at rt for 30 min, then tert-butylamine (273 mg, 3.73 mmol) was added and the solution was stirred for another 0.5 h. The mixture was quenched with water and extracted three times with EA. The combined organic layers were washed with water and brine consecutively, dried over Na₂SO₄, filtered, concentrated and purified by CC (PE/EA = 5/1) to give intermediate 10b (410 mg, 61%) as a colorless solid.

A solution of intermediate 10b (100 mg, 463 µmol) and CuBr₂·2 H₂O (124 mg, 556 µmol) in ACN (10 mL) was stirred at rt for 1.5 h. The mixture was quenched with sat. aq. NH₄Cl and extracted twice with EA. The combined organic layers were washed with brine, dried over Na₂SO₄, filtered, concentrated and purified by CC (PE/EA = 20/1) to give intermediate 10c (50 mg, 37%) as a yellow solid.

To a solution of intermediate 10c (50 mg, 169 µmol), P18 (59.5 mg, 203 µmol), K₂CO₃ (58 mg, 423 µmol) and TBAB (10 mg) in a mixture of 1,4-dioxane (1 mL) and water (0.5 mL) was added Pd(PPh₃)₂Cl₂ (10 mg) under N₂ and the solution was heated to 85°C for 1 h under microwave irradiation (120 W). After cooling to rt the resulting solution was poured into a mixture of water and EA and the aq. phase was extracted twice with EA. The combined organic layers were washed with water and brine, dried over Na₂SO₄, filtered, concentrated and purified by CC (PE/EA = 5/1) to give intermediate 10d (30 mg, 38%) as a colorless solid.

To a solution of intermediate 10d (156 mg, 337 µmol) in a mixture of DMSO (1.5 mL) and water (one drop) was added KOtBu (76 mg, 674 µmol) and the solution was stirred at 80°C overnight. The mixture was quenched with water, the pH was adjusted to 5 with 1M HCl and extracted twice with DCM. The combined organic layers were washed with water three times and brine consecutively, dried over Na₂SO₄, filtered and concentrated to give intermediate 10e (143 mg, 98%) as a colorless solid.

A solution of intermediate 10e (143 mg, 329 µmol), HATU (150 mg, 394 µmol) and DIPEA (127 mg, 986 µmol) in dry DMF (2 mL) was stirred for 30 min at rt, then 4-aminotetrahydropyran (40 mg, 394 µmol) was added and the solution was stirred for another 0.5 h. The mixture was quenched with water and extracted twice with EA. The combined organic layers were washed with water three times and brine consecutively, dried over Na₂SO₄, filtered, concentrated and purified by prep. HPLC to give 10 (25 mg, 15%) as a colorless solid. ¹H-NMR (CDCl₃, 400 MHz) δ: 0.54-0.60 (2H, m), 0.96-0.98 (3H, m), 1.25-1.28 (4H, m), 1.44-1.51 (13H, m), 1.97-2.01 (2H, m), 2.64 (3H, s), 3.50-3.55 (4H, m), 3.97-3.99 (2H, m), 4.15-4.4.19 (1H, m), 5.58-5.60 (1H, d, J = 8.0 Hz), 5.67 (1H, s), 6.35 (1H, s), 6.63-6.67 (1H, m), 6.83 (1H, s), 6.99-7.03 (1H, m), 7.73 (1H, d, J = 7.6 Hz), 8.37 (1H, d, J = 9.2 Hz). MS: 519.2 (M+1).

The following Example was prepared similar as in Example 10: # Structure Analytical data 10/1 ¹H-NMR (CDCl₃, 400 MHz) δ: 0.61-0.63 (2H, m), 0.96-0.98 (3H, m), 1.34-1.36 (4H, m), 1.53-1.55 (2H, m), 1.64-1.72 (6H, m), 2.62 (3H, s), 3.51-3.53 (2H, d, J = 7.2 Hz), 3.70-3.73 (4H, m), 4.56-4.59 (2H, m), 4.98-5.01 (2H, m), 5.20-5.22 (1H, m), 6.21-6.22 (1H, m), 6.43 (1H, s), 6.60-6.64 (1H, m), 6.87 (1H, s), 6.93-6.97 (1H, m), 7.70-7.72 (1H, m), 7.90-7.92 (1H, m). MS: 503.1 (M+1)⁺.